Certain xcex1-hydroxy-xcex3-[[(carbocyclic- or heterocyclic-substituted)amino]carbonyl]alkanamide derivatives are described as inhibitors of HIV protease and inhibitors of HIV replication. These compounds are useful in the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described. These compounds are effective against HIV viral mutants which are resistant to HIV protease inhibitors currently used for treating AIDS and HIV infection.

The present invention is directed to xcex1-hydroxy-xcex3-[[(carbocyclic- or heterocyclic-substituted)amino]carbonyl]alkanamide derivatives, their pharmaceutically acceptable salts, their synthesis, and their use as inhibitors of HIV protease. The compounds of the present invention are useful for preventing or treating infection by HIV and for treating AIDS.
References are made throughout this application to various publications in order to more fully describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference in their entireties.
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destriction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl et al., Proc. Nat""l Acad. Sci. 1988, 85: 4686, demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicated that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner et al., Nature 1985, 313: 277]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh et al., EMBO J. 1985, 4: 1267; Power et al., Science 1986, 231: 1567; Pearl et al., Nature 1987, 329: 351].
Several HIV protease inhibitors are presently in clinical use for the treatment of AIDS and HIV infection, including indinavir (see U.S. Pat. No. 5,413,999), nelfinavir (U.S. Pat. No. 5,484,926), saquinavir (U.S. Pat. No. 5,196,438), and ritonavir (U.S. Pat. No. 5,484,801). Each of these protease inhibitors is a peptidomimetic, competitive inhibitor of the viral protease which prevents cleavage of the HIV gag-pol polyprotein precursor. Indinavir, for example, has been found to be highly effective in reducing HIV viral loads and increasing CD4 cell counts in HIV-infected patients, when used in combination with nucleoside reverse transcriptase inhibitors. See, for example, Hammer et al., New England J. Med. 1997, 337: 725-733 and Gulick et al., New England J. Med. 1997, 337: 734-739.
A substantial and persistent problem in the treatment of AIDS has been the ability of the HIV virus to develop resistance to the therapeutic agents employed to treat the disease. Resistance to HIV-1 protease inhibitors has been associated with 25 or more amino acid substitutions in both the protease and the cleavage sites. Many of these viral variants are resistant to all of the HIV protease inhibitors currently in clinical use. See Condra et al., Drug Resistance Updates 1998, 1: 1-7; Condra et al., Nature 1995, 374: 569-571; Condra et al., J. Virol. 1996, 70: 8270-8276; Patrick et al., Antiviral Ther. 1996, Suppl. 1: 17-18; and Tisdale et al., Antimicrob. Agents Chemother. 1995, 39: 1704-1710.
Attempts to address the resistance issue with xe2x80x9csalvage therapyxe2x80x9d consisting of high doses of multiple protease inhibitors have only been moderately successful due to the high level of cross resistance and toxicities associated with these protease inhibitors. Accordingly, there remains a need for new protease inhibitors having improved effectiveness against the viral variants.
The present invention is directed to novel protease inhibitors which are much more potent against HIV viral mutants than the known protease inhibitors.
The present invention provides a novel group of xcex1-hydroxy-xcex3-[[(carbocyclic- or heterocyclic-substituted)amino]carbonyl]alkanamide derivatives which are potent inhibitors of HIV protease including mutant forms thereof that are resistant to known protease inhibitors. These compounds are useful in the inhibition of HIV protease, the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS and/or ARC, when employed as compounds or pharmaceutically acceptable salts or hydrates (when appropriate) thereof, optionally as pharmaceutical composition ingredients, and optionally in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. More particularly, the present invention includes a compound of Formula (I):
wherein
R1, R2, and R3 are as defined in (A) or in (B) as follows:
(A) R1 is
1) hydrogen,
2) C1-C6 alkyl, or
3) substituted C1-C6 alkyl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) aryl,
e) substituted aryl, wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl, and aryl,
f) heterocycle, and
g) substituted heterocycle, wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl, and aryl;
R2 and R3 are each independently selected from
1) hydrogen,
2) C1-C6 alkyl,
3) substituted C1-C6 alkyl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) aryl,
e) substituted aryl, wherein each substituent is independently selected from cyano, halo, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl, and aryl,
f) heterocycle, and
g) substituted heterocycle, wherein each substituent is independently selected from cyano, halo, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl, and aryl,
4) aryl,
5) substituted aryl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) aryl,
e) substituted aryl wherein each substituent is independently selected from cyano, halo, hydroxy, C1-C4 alkyl, and fluorinated C1-C4 alkyl,
f) heterocycle,
g) substituted heterocycle wherein each substituent is independently selected from cyano, halo, hydroxy, C1-C4 alkyl, and fluorinated C1-C4 alkyl,
6) heterocycle, and
7) substituted heterocycle wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) aryl,
e) substituted aryl wherein each substituent is independently selected from cyano, halo, hydroxy, C1-C4 alkyl, and fluorinated C1-C4 alkyl,
f) heterocycle, and
g) substituted heterocycle wherein each substituent is independently selected from cyano, halo, hydroxy, C1-C4 alkyl, and fluorinated C1-C4 alkyl;
or R2 and R3 together with the carbon to which they are attached form C3-C6 cycloalkyl which is optionally substituted with one or more substituents independently selected from
1) hydroxy
2) C1-C6 alkyl,
3) C1-C3 alkoxy,
4) aryl,
5) substituted aryl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl,
e) fluorinated C1-C4 alkyl,
f) aryl,
g) substituted aryl wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and fluorinated C1-C4 alkyl,
h) heterocycle,
i) substituted heterocycle wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and fluorinated C1-C4 alkyl,
6) heterocycle, and
7) substituted heterocycle wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl,
e) fluorinated C1-C4 alkyl,
f) aryl,
g) substituted aryl wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and fluorinated C1-C4 alkyl,
h) heterocycle, and
i) substituted heterocycle wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and fluorinated C1-C4 alkyl,
or
(B) R1 and R2 together with the nitrogen to which R1 is attached and the carbon to which R2 is attached form a 4- to 8-membered monocyclic heterocycle containing from 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein at least one heteroatom in the monocyclic heterocycle is nitrogen and wherein the monocyclic heterocycle is optionally substituted with one or more substituents independently selected from
1) halo
2) hydroxy
3) C1-C6 alkyl,
4) C1-C3 alkoxy,
5) aryl, and
6) heterocycle;
and R3 is as defined above in (A) when R3 is independent from and not joined to R2;
R4 is (CH2)mRa, wherein m is an integer from zero to 3 and Ra is
1) hydrogen,
2) C1-C6 alkyl,
3) substituted C1-C6 alkyl wherein each substituent is independently selected from
a) halo,
b) hydroxy, and
c) C1-C3 alkoxy,
4) aryl,
5) substituted aryl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl,
e) fluorinated C1-C4 alkyl,
f) aryl,
g) substituted aryl wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and fluorinated C1-C4 alkyl,
h) heterocycle, and
i) substituted heterocycle wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and fluorinated C1-C4 alkyl,
6) heterocycle,
7) substituted heterocycle wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl,
e) fluorinated C1-C4 alkyl,
f) aryl,
g) substituted aryl wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and fluorinated C1-C4 alkyl,
h) heterocycle, and
i) substituted heterocycle wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and fluorinated C1-C4 alkyl;
R5 is chroman, thiochroman, indanyl, dioxoisothiochroman, cyclopentyl, substituted chroman, substituted thiochroman, substituted indanyl, substituted dioxothiochroman, or substituted cyclopentyl; wherein each of the substituents on substituted chroman, thiochroman, indanyl, dioxoisothiochroman, or cyclopentyl is independently selected from halogen, cyano, hydroxy, C1-C6 alkyl, fluorinated C1-C6 alkyl, C1-C4 alkoxy, or fluorinated C1-C4 alkoxy; and
R6 and R7 are each independently
1) hydrogen,
2) C1-C6 alkyl, or
3) substituted C1-C6 alkyl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) aryl,
d) substituted aryl, wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl, and aryl,
e) heterocycle, and
f) substituted heterocycle, wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl, and aryl,
or
R6 and R7 together with the nitrogen to which they are attached form C3-C6 azacycloalkyl which is optionally substituted with one or more substituents independently selected from
1) halo,
2) hydroxy,
3) C1-C6 alkyl,
4) C1-C3 alkoxy,
5) aryl,
6) substituted aryl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl, and
e) fluorinated C1-C4 alkyl
7) heterocycle, and
8) substituted heterocycle wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl, and
e) fluorinated C1-C4 alkyl;
or pharmaceutically acceptable salt thereof.
The present invention also includes pharmaceutical compositions containing a compound of the present invention and methods of preparing such pharmaceutical compositions. The present invention further includes methods of treating AIDS, methods of preventing infetion by HIV, and methods of treating infection by HIV.
These and other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples, and appended claims.
The present invention includes the compounds of Formula (I) above. These compounds and their pharmaceutically acceptable salts thereof are HIV protease inhibitors.
A first embodiment of the invention is a compound of Formula (I), wherein R1, R2, and R3 are as defined in (A); and
all of variables are as originally defined above;
or a pharmaceutically acceptable salt thereof.
A second embodiment of the invention is a compound of Formula (I),
wherein
R1 is hydrogen or C1-C4 alkyl;
R2 and R3 are each independently selected from hydrogen or C1-C4 alkyl; or R2 and R3 together with the carbon to which they are attached form C3-C6 cycloalkyl;
R4 is (CH2)mRa, wherein m is an integer from zero to 3 and Ra is
1) hydrogen,
2) C1-C4 alkyl,
3) substituted C1-C4 alkyl wherein each substituent is independently selected from
a) halo,
b) hydroxy, and
c) C1-C3 alkoxy,
4) phenyl,
5) mono- or di- or tri-substituted phenyl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl,
e) (CH2)0-3CF3,
f) phenyl,
g) mono- or di- or tri-substituted phenyl, wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3,
h) heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, and tetrazolyl, and
i) mono- or di- or tri-substituted heterocycle, wherein heterocycle is selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, and tetrazolyl, and wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3;
6) heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, and furopyridyl, or
7) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, and furopyridyl, and wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl,
e) (CH2)0-3CF3,
f) phenyl,
g) mono- or di- or tri-substituted phenyl wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3,
h) heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, and tetrazolyl, and
i) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, and tetrazolyl, and wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3;
R5 is chroman, thiochroman, indanyl, dioxoisothiochroman, cyclopentyl, substituted chroman, substituted thiochroman, substituted indanyl, substituted dioxothiochroman, or substituted cyclopentyl; wherein each of the substituents on substituted chroman, thiochroman, indanyl, dioxoisothiochroman, or cyclopentyl is independently selected from halogen, cyano, hydroxy, C1-C4 alkyl, (CH2)0-3CF3, C1-C4 alkoxy, or (CH2)0-3OCF3; and
R6 and R7 are each independently
1) hydrogen,
2) C1-C4 alkyl, or
3) substituted C1-C4 alkyl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) phenyl,
d) mono- or di- or tri-substituted phenyl, wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, (CH2)0-3CF3, and phenyl,
e) heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, and tetrazolyl, and
f) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, and tetrazolyl, and wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, (CH2)0-3CF3, and phenyl;
or
R6 and R7 together with the nitrogen to which they are attached form C3-C6 azacycloalkyl which is optionally substituted with one or more substituents independently selected from
1) halo
2) hydroxy
3) C1-C4 alkyl, and
4) C1-C3 alkoxy;
or a pharmaceutically acceptable salt thereof.
A third embodiment of the invention is a compound of Formula (I), wherein
R4 is (CH2)mRa, wherein m is an integer from zero to 3 and Ra is
1) hydrogen,
2) C1-C4 alkyl,
3) substituted C1-C4 alkyl wherein each substituent is independently selected from
a) halo,
b) hydroxy, and
c) C1-C3 alkoxy,
4) phenyl,
5) mono- or di- or tri-substituted phenyl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl,
e) (CH2)0-3CF3,
f) phenyl,
g) mono- or di- or tri-substituted phenyl, wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3,
h) heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, and tetrazolyl, and
i) mono- or di- or tri-substituted heterocycle, wherein heterocycle is selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, and tetrazolyl, and wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3;
6) heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, and tetrazolyl, or
7) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, and tetrazolyl, and wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl,
e) (CH2)0-3CF3,
f) phenyl,
g) mono- or di- or tri-substituted phenyl wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3,
h) heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, and tetrazolyl, and
i) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, and tetrazolyl, and wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3;
R6 and R7 are each independently
1) hydrogen,
2) C1-C4 alkyl, or
3) substituted C1-C4 alkyl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) phenyl,
d) mono- or di- or tri-substituted phenyl, wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, (CH2)0-3CF3, and phenyl,
e) heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, and tetrazolyl, and
f) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, and tetrazolyl, and wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, (CH2)0-3CF3, and phenyl;
or
R6 and R7 together with the nitrogen to which they are attached form C3-C6 azacycloalkyl which is optionally substituted with one or more substituents independently selected from
1) halo
2) hydroxy
3) C1-C4 alkyl, and
4) C1-C3 alkoxy;
and all other variables are as defined in the second embodiment;
or a pharmaceutically acceptable salt thereof.
A first class of the invention is a compound of Formula (I), wherein
R5 is chroman, indanyl, substituted chroman, or substituted indanyl;
and all other variables are as defined in the second embodiment;
or a pharmaceutically acceptable salt thereof.
In a sub-class of the first class is a compound of Formula (I), wherein
Ra is
1) C1-C4 alkyl,
2) substituted C1-C4 alkyl wherein each substituent is independently selected from
a) halo,
b) hydroxy, and
c) C1-C3 alkoxy,
3) phenyl,
4) mono- or di- or tri-substituted phenyl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl,
e) CF3,
f) phenyl,
g) mono- or di- or tri-substituted phenyl, wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and CF3,
h) heterocycle selected from pyridyl, pyrazinyl and pyrimidinyl, and
i) mono- or di- or tri-substituted heterocycle, wherein heterocycle is selected from pyridyl, pyrazinyl, and pyrimidinyl, and wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and CF3;
5) heterocycle selected from pyridyl, pyrazinyl and pyrimidinyl, or
6) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyridyl, pyrazinyl and pyrimidinyl; and wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl,
e) CF3,
f) phenyl,
g) mono- or di- or tri-substituted phenyl wherein each substituent is independently selected from cyano, halo, hydroxy, C1-C4 alkyl, and CF3,
h) heterocycle selected from pyridyl, pyrazinyl and pyrimidinyl, and
i) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyridyl, pyrazinyl and pyrimidinyl, and wherein each substituent is independently selected from cyano, halo, hydroxy, C1-C4 alkyl, and CF3; and
R6 and R7 are each independently
1) hydrogen,
2) C1-C6 alkyl, or
3) substituted C1-C6 alkyl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) phenyl,
d) mono- or di- or tri-substituted phenyl, wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and CF3,
e) heterocycle selected from pyridyl, pyrazinyl and pyrimidinyl, and
f) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyridyl, pyrazinyl and pyrimidinyl, and wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3; and
all other variables are as defined in the first class;
or a pharmaceutically acceptable salt thereof.
In another sub-class of the first class is a compound of Formula (I), wherein
R4 is CH2Ra, wherein Ra is
1) phenyl,
2) mono- or di- or tri-substituted phenyl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl, and
e) CF3,
3) heterocycle selected from pyridyl, pyrazinyl and pyrimidinyl, or
4) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyridyl, pyrazinyl and pyrimidinyl; and wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl, and
e) CF3;
and all other variables are as defined in the first class;
or a pharmaceutically acceptable salt thereof.
A second class of the invention is a compound of Formula (I), wherein
R5 is chroman, indanyl, substituted chroman, or substituted indanyl;
and all other variables are as defined in the third embodiment;
or a pharmaceutically acceptable salt thereof.
The second class of the invention has sub-classes analgous to the sub-classes set forth above for the first class of the invention.
Exemplifying the invention are compounds selected from the group consisting of
(xcex1S,xcex3R)-xcex3-[[((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)amino]carbonyl]-xcex1-hydroxy-N-[1-[[[(2-methylphenyl)methyl]amino]carbonyl]cyclopentyl]benzene pentanamide;
(xcex1S,xcex3R)-xcex3-[[((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)amino]carbonyl]-xcex1-hydroxy-N-[1,1-dimethyl-2-[[(2-methylphenyl)methyl]amino]-2-oxoethyl] benzenepentanamide;
and pharmaceutically acceptable salts thereof.
A fourth embodiment of the invention is a compound of Formula (II):
wherein X is
1) S(O)p wherein p is an integer equal to 0,1, or 2
2) O, or
3) CRbRc, wherein Rb and Rc are each independently
a) hydrogen,
b) hydroxy,
c) halo,
d) C1-C4 alkyl,
e) C1-C3 alkoxy,
f) aryl, or
g) heterocycle;
Y is CRdRe, wherein Rd and Re are each independently
a) hydrogen,
b) halo, or
c) C1-C4 alkyl;
n is an integer equal to 0, 1, or 2;
and all other variables are as originally defined;
or a pharmaceutically acceptable salt thereof.
In a fifth embodiment of the invention, the compound is of Formula (II), wherein
R4 is (CH2)mRa, wherein m is an integer from zero to 3 and Ra is
1) hydrogen,
2) C1-C4 alkyl,
3) substituted C1-C4 alkyl wherein each substituent is independently selected from
a) halo,
b) hydroxy, and
c) C1-C3 alkoxy,
4) phenyl,
5) mono- or di- or tri-substituted phenyl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl,
e) (CH2)0-3CF3,
f) phenyl,
g) mono- or di- or tri-substituted phenyl, wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3,
h) heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, and tetrazolyl, and
i) mono- or di- or tri-substituted heterocycle, wherein heterocycle is selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, and tetrazolyl, and wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3;
6) heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, and furopyridyl, or
7) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, and furopyridyl, and wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl,
e) (CH2)0-3CF3,
f) phenyl,
g) mono- or di- or tri-substituted phenyl wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3,
h) heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, and tetrazolyl, and
i) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, and tetrazolyl, and wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3;
R5 is chroman, thiochroman, indanyl, dioxoisothiochroman, cyclopentyl, substituted chroman, substituted thiochroman, substituted indanyl, substituted dioxothiochroman, or substituted cyclopentyl; wherein each of the substituents on substituted chroman, thiochroman, indanyl, dioxoisothiochroman, or cyclopentyl is independently selected from halogen, cyano, hydroxy, C1-C4 alkyl, (CH2)0-3CF3, C1-C4 alkoxy, or (CH2)0-3OCF3;
R6 and R7 are each independently
1) hydrogen,
2) C1-C4 alkyl, or
3) substituted C1-C4 alkyl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) phenyl, and
d) mono- or di- or tri-substituted phenyl, wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3,
e) heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, and tetrazolyl, and
f) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, and tetrazolyl, and wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3;
or
R6 and R7 together with the nitrogen to which they are attached form C3-C6 azacycloalkyl which is optionally substituted with one or more substituents independently selected from
1) halo
2) hydroxy
3) C1-C4 alkyl, and
4) C1-C3 alkoxy;
and all other variables are as defined in the second embodiment;
or a pharmaceutically acceptable salt thereof.
A sixth embodiment of the invention is a compound of Formula (II) wherein
R4 is (CH2)mRa, wherein m is an integer from zero to 3 and Ra is
1) hydrogen,
2) C1-C4 alkyl,
3) substituted C1-C4 alkyl wherein each substituent is independently selected from
a) halo,
b) hydroxy, and
c) C1-C3 alkoxy,
4) phenyl,
5) mono- or di- or tri-substituted phenyl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl,
e) (CH2)0-3CF3,
f) phenyl,
g) mono- or di- or tri-substituted phenyl, wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3,
h) heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, and tetrazolyl, and
i) mono- or di- or tri-substituted heterocycle, wherein heterocycle is selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, and tetrazolyl, and wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3;
6) heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, and tetrazolyl, or
7) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, and tetrazolyl, and wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl,
e) (CH2)0-3CF3,
f) phenyl,
g) mono- or di- or tri-substituted phenyl wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3,
h) heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, traizolyl, and tetrazolyl, and
i) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, and tetrazolyl, and wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3;
and all other variables are as defined in the third embodiment;
or a pharmaceutically acceptable salt thereof.
A seventh embodiment of the invention is a compound of Formula (III):
wherein
X is S, O or CRbRc, wherein Rb and Rc are each independently hydrogen, hydroxy, halo, or C1-C3 alkoxy;
and all other variables are as defined in the fifth embodiment;
or a pharmaceutically acceptable salt thereof.
An eighth embodiment of the invention is a compound of Formula (III), wherein
X is S, O or CRbRc, wherein Rb and Rc are each independently hydrogen, hydroxy, halo, or C1-C3 alkoxy;
and all other variables are as defined in the sixth embodiment;
or a pharmaceutically acceptable salt thereof.
A third class of the invention is a compound of Formula (III), wherein
R5 is chroman, indanyl, cyclopentyl, substituted chroman, substituted indanyl, or substituted cyclopentyl;
and all other variables are as defined in the seventh embodiment;
or a pharmaceutically acceptable salt thereof.
A fourth class of the invention is a compound of Formula (III), wherein
R5 is chroman, indanyl, cyclopentyl, substituted chroman, substituted indanyl, or substituted cyclopentyl;
and all other variables are as defined in the eighth embodiment;
or a pharmaceutically acceptable salt thereof.
A fifth class of the invention is a compound of Formula (III), wherein
Ra is
1) C1-C4 alkyl,
2) substituted C1-C4 alkyl wherein each substituent is independently selected from
a) halo,
b) hydroxy, and
c) C1-C3 alkoxy,
3) phenyl,
4) mono- or di- or tri-substituted phenyl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl,
e) CF3,
f) phenyl,
g) mono- or di- or tri-substituted phenyl, wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and CF3,
h) heterocycle selected from pyridyl, pyrazinyl and pyrimidinyl, and
i) mono- or di- or tri-substituted heterocycle, wherein heterocycle is selected from pyridyl, pyrazinyl, and pyrimidinyl, and wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and CF3;
5) heterocycle selected from pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, thiazolyl, and furopyridyl, or
6) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, thiazolyl, and furopyridyl; and wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl,
e) CF3,
f) phenyl,
g) mono- or di- or tri-substituted phenyl wherein each substituent is independently selected from cyano, halo, hydroxy, C1-C4 alkyl, and CF3,
h) heterocycle selected from pyridyl, pyrazinyl and pyrimidinyl, and
i) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyridyl, pyrazinyl and pyrimidinyl, and wherein each substituent is independently selected from cyano, halo, hydroxy, C1-C4 alkyl, and CF3; and
R6 and R7 are each independently
1) hydrogen,
2) C1-C4 alkyl, or
3) substituted C1-C4 alkyl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) phenyl,
d) mono- or di- or tri-substituted phenyl, wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and CF3,
e) heterocycle selected from pyridyl, pyrazinyl and pyrimidinyl, and
f) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyridyl, pyrazinyl and pyrimidinyl, and wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3;
and all other variables are as defined in the third class;
or a pharmaceutically acceptable salt thereof.
In one aspect of the fifth class, R4 is CH2Ra, wherein Ra is
1) phenyl,
2) mono- or di- or tri-substituted phenyl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl, and
e) CF3,
3) heterocycle selected from pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, thiazolyl, and furopyridyl, or
4) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, thiazolyl, and furopyridyl; and wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl, and
e) CF3.
In another aspect of the fifth class, X is S or CRbRc.
A sixth class of the invention is a compound of Formula (III), wherein
Ra is
1) C1-C4 alkyl,
2) substituted C1-C4 alkyl wherein each substituent is independently selected from
a) halo,
b) hydroxy, and
c) C1-C3 alkoxy,
3) phenyl,
4) mono- or di- or tri-substituted phenyl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl,
e) CF3,
f) phenyl,
g) mono- or di- or tri-substituted phenyl, wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and CF3,
h) heterocycle selected from pyridyl, pyrazinyl and pyrimidinyl, and
i) mono- or di- or tri-substituted heterocycle, wherein heterocycle is selected from pyridyl, pyrazinyl, and pyrimidinyl, and wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and CF3;
5) heterocycle selected from pyridyl, pyrazinyl, pyrimidinyl, or
6) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyridyl, pyrazinyl, and pyrimidinyl; and wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl,
e) CF3,
f) phenyl,
g) mono- or di- or tri-substituted phenyl wherein each substituent is independently selected from cyano, halo, hydroxy, C1-C4 alkyl, and CF3,
h) heterocycle selected from pyridyl, pyrazinyl and pyrimidinyl, and
i) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyridyl, pyrazinyl and pyrimidinyl, and wherein each substituent is independently selected from cyano, halo, hydroxy, C1-C4 alkyl, and CF3; and
R6 and R7 are each independently
1) hydrogen,
2) C1-C4 alkyl, or
3) substituted C1-C4 alkyl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) phenyl,
d) mono- or di- or tri-substituted phenyl, wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and CF3,
e) heterocycle selected from pyridyl, pyrazinyl and pyrimidinyl, and
f) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyridyl, pyrazinyl and pyrimidinyl, and wherein each substituent is independently selected from halo, hydroxy, C1-C4 alkyl, and (CH2)0-3CF3;
and all other variables are as defined in the fourth class;
or a pharmaceutically acceptable salt thereof.
In one aspect of the sixth class, R4 is CH2Ra, wherein Ra is
1)phenyl,
2) mono- or di- or tri-substituted phenyl wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl, and
e) CF3,
3) heterocycle selected from pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, and furopyridyl, or
4) mono- or di- or tri-substituted heterocycle wherein heterocycle is selected from pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, and furopyridyl; and wherein each substituent is independently selected from
a) halo,
b) hydroxy,
c) C1-C3 alkoxy,
d) C1-C4 alkyl, and
e) CF3.
In another aspect of the sixth class, X is S or CRbRc.
Also exemplifying the invention are compounds selected from the group consisting of
(4R)-3-[(2S,4R)-5-[((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl) pentyl]-5,5-dimethyl-N-[(2-methylphenyl) methyl]-4-thiazolidinecarboxamide;
(4R)-3-[(2S,4R)-5-[((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl)pentyl]-5,5-dimethyl-N-(2,2,2-trifluoroethyl)-4-thiazolidinecarboxamide;
(4R)-3-[(2S,4R)-5-[((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl) pentyl]-5,5-dimethyl-N-(1,1-dimethylethyl)-4-thiazolidinecarboxamide;
(4R)-3-[(2S,4R)-5-[((1S,2R)-2,3-dihydro-2-hydroxy-1H-inden-1-yl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl) pentyl]-5,5-dimethyl-N-(2,2,2-trifluoroethyl)-4-thiazolidinecarboxamide;
(4R)-3-[(2S,4R)-5-[((1S,2R)-2,3-dihydro-2-hydroxy-1H-inden-1-yl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl) pentyl]-5,5-dimethyl-N-(1,1-dimethylethyl)-4-thiazolidinecarboxamide;
(4R)-3-[(2S,4R)-5-[((1S,2R)-2,3-dihydro-2-hydroxy-1H-inden-1-yl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl) pentyl]-5,5-dimethyl-N-[(2-methylphenyl)-methyl]-4-thiazolidinecarboxamide;
(2S)-1-[(2S,4R)-5-[((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl) pentyl]-N-[(2-methylphenyl)-methyl]-2-pyrrolidinecarboxamide;
(4R)-3-[(2S,4R)-5-[((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl) pentyl]-5,5-dimethyl-N-(4-pyridinylmethyl)-4-thiazolidinecarboxamide;
(2S)-1-[(2S,4R)-5-[((1S,2R)-2,3-dihydro-2-hydroxy-1H-inden-1-yl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl) pentyl]-N-[(2-methylphenyl)-methyl]-2-pyrrolidinecarboxamide;
(4R)-3-[(2S,4R)-5-[((1S,2R)-2,3-dihydro-2-hydroxy-1H-inden-1-yl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl) pentyl]-5,5-dimethyl-N-(3-pyridinylmethyl)-4-thiazolidinecarboxamide;
(4R)-3-[(2S,4R)-5-[((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl) pentyl]-5,5-dimethyl-N-(2-phenylethyl)-4-thiazolidinecarboxamide;
(4R)-3-[(2S,4R)-5-[((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)amino]-2-hydroxy-1,5-dioxo-4-(3-pyridinylmethyl) pentyl]-5,5-dimethyl-N-[(2-methylphenyl methyl]-4-thiazolidinecarboxamide;
(4R)3-[(2S,4R)-5-[((1S,2R,5R)-5-methyl-2-hydroxy-1-cyclopentyl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl) pentyl]-5,5-dimethyl-N-[(2-methylphenyl)-methyl]-4-thiazolidinecarboxamide;
(2S,4S)-1-[(2S,4R)-5-[((1S,2R)-2,3-dihydro-2-hydroxy-1H-inden-1-yl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl) pentyl]-N-[(2-methylphenyl)methyl]-4-chloro-2-pyrrolidinecarboxamide;
and pharmaceutically acceptable salts thereof.
Also exemplifying the invention are compounds selected from the group consisting of
(4R)-3-[(2S,4R)-5-[((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl) pentyl]-3,3-dimethyl-N-[(2,6-dimethylphenyl)-methyl]-2-pyrrolidinecarboxamide;
(4R)-3-[(2S,4R)-5-[((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl) pentyl]-3,3-dimethyl-N-[(3-methyl-2-pyridylmethyl)]-2-pyrrolidinecarboxamide;
(4R)-3-[(2S,4R)-5-[((3S,4S)-3,4-dihydro-3-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl) pentyl]-5,5-dimethyl-N-[(2,6-dimethylphenyl) methyl]-4-oxazolidinecarboxamide;
(4R)-3-[(2S,4R)-5-[((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl) pentyl]-5,5-dimethyl-N-[(2,6-dimethylphenyl) methyl]-4-thiazolidinecarboxamide;
(4R)-3-[(2S,4R)-5-[((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl) pentyl]-5,5-dimethyl-N-[(3-methyl-2-pyridinylmethyl)]-4-thiazolidinecarboxamide;
(4R)-3-[(2S,4R)-5-[((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl) pentyl]-5,5-dimethyl-N-[(3,5-dimethyl-4-isoxazolemethyl)]-4-thiazolidinecarboxamide;
(4R)-3-[(2S,4R)-5-[((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)amino]-2-hydroxy-1,5-dioxo-4-(phenylmethyl) pentyl]-5,5-dimethyl-N-[(2,6-dimethylphenyl) methyl]-4-thiazolidinecarboxamide-1,1-dioxide;
(4R)-N-[(2-chloro-6-methylphenyl)methyl]-3-[(2S,4S)-5-[((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl) amino]-4-(furo[2,3-c]pyridin-2-ylmethyl)-2-hydroxy-1,5-dioxopentyl]-5,5-dimethyl-4-thiazolidinecarboxamide;
(4R)-N-[(2-chloro-6-methylphenyl)methyl]-3-[(2S,4S)-5-[((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl) amino]-2-hydroxy-4-(5-oxazolymethyl)-1,5-dioxopentyl]-5,5-dimethyl-4-thiazolidinecarboxamide;
and pharmaceutically acceptable salts thereof.
Other embodiments of the present invention include the following:
(a) A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier.
(b) A pharmaceutical composition made by combining a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier.
(c) The pharmaceutical composition of (a), wherein the composition further comprises a therapeutically effective amount of at least one HIV infection/AIDS treatment agent selected from the group consisting of HIV/AIDS antiviral agents, immunomodulators, and anti-infective agents.
(d) The pharmaceutical composition of (a), wherein the composition further comprises a therapeutically effective amount of at least one antiviral selected from the group consisting of non-nucleoside HIV reverse transcriptase inhibitors and nucleoside HIV reverse transcriptase inhibitors.
(e) The pharmaceutical composition of (d), further comprising a therapeutically effective amount of an additional HIV protease inhibitor.
(f) A method of inhibiting HIV protease in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of Formula (I).
(g) A method of preventing or treating infection by HIV in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of Formula (I).
(h) The method of (g), wherein the compound of Formula (I) is administered in combination with a therapeutically effective amount of at least one antiviral selected from the group consisting of non-nucleoside HIV reverse transcriptase inhibitors and nucleoside HIV reverse transcriptase inhibitors.
(i) A method of treating AIDS in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of Formula (I).
(j) The method of (i), wherein the compound is administered in combination with a therapeutically effective amount of at least one HIV infection/AIDS treatment agent selected from the group consisting of HIV/AIDS antiviral agents, immunomodulators, and anti-infective agents.
(k) The method of (i), wherein the compound is administered in combination with a therapeutically effective amount of at least one antiviral selected from the group consisting of non-nucleoside HIV reverse transcriptase inhibitors and nucleoside HIV reverse transcriptase inhibitors.
(l) A method of inhibiting HIV protease in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the composition of (a) or (b).
(m) A method of preventing or treating infection by HIV in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the composition of (a) or (b) or (c) or (d) or (e).
(n) A method of treating AIDS in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the composition of (a) or (b) or (c) or (d) or (e).
Additional embodiments of the invention include the pharmaceutical compositions and methods set forth in (a)-(n) above, wherein the compound employed therein is a compound of one of the embodiments, classes, or sub-classes of compounds described above.
As used herein, the term xe2x80x9cC1-C6 alkylxe2x80x9d means linear or branched chain alkyl groups having from 1 to 6 carbon atoms and includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. xe2x80x9cC1-C4 alkylxe2x80x9d means n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
The term xe2x80x9cC1-C6 alkoxyxe2x80x9d means an xe2x80x94O-alkyl group wherein alkyl is C1 to C6 alkyl as defined above. xe2x80x9cC1-C4 alkoxyxe2x80x9d has an analogous meaning; i.e., it is an alkoxy group selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and sec-butoxy. Similarly, xe2x80x9cC1-C3 alkoxyxe2x80x9d is selected from methoxy, ethoxy, n-propoxy, and isopropoxy.
The term xe2x80x9cC3-C7 cycloalkylxe2x80x9d means a cyclic ring of an alkane having three to seven total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl). The term xe2x80x9cC3-C6 cycloalkylxe2x80x9d refers to a cyclic ring selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. xe2x80x9cC3-C5 cycloalkylxe2x80x9d has an analogous meaning.
The term xe2x80x9chalogenxe2x80x9d (which may alternatively be referred to as xe2x80x9chaloxe2x80x9d) refers to fluorine, chlorine, bromine and iodine (alternatively, fluoro, chloro, bromo, and iodo).
The term xe2x80x9cfluorinated C1-C6 alkylxe2x80x9d (which may alternatively be referred to as xe2x80x9cC1-C6 fluoroalkylxe2x80x9d) means a C1 to C6 linear or branched alkyl group as defined above with one or more fluorine substituents. The term xe2x80x9cfluorinated C1-C4 alkylxe2x80x9d has an analogous meaning. Representative examples of suitable fluoroalkyls include the series (CH2)0-3CF3 (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.), 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 3,3,3-trifluoroisopropyl, 1,1,1,3,3,3-hexafluoroisopropyl, and perfluorohexyl.
The term xe2x80x9cfluorinated C1-C6 alkoxyxe2x80x9d (which may alternatively be referred to as xe2x80x9cC1-C6 fluoroalkoxyxe2x80x9d) means a C1-C6 alkoxy group as defined above wherein the alkyl moiety has one or more fluorine substituents. The terms xe2x80x9cfluorinated C1-C4 alkoxyxe2x80x9d and xe2x80x9cfluorinated C1-C3 alkoxyxe2x80x9d have analogous meanings. Representative examples include the series O(CH2)0-3CF3 (i.e., trifluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoro-n-propoxy, etc.), 1,1,1,3,3,3-hexafluoroisopropoxy, and so forth.
The term xe2x80x9carylxe2x80x9d refers to aromatic mono- and poly-carbocyclic ring systems, wherein the carbocyclic rings in the polyring systems may be fused or attached to each other via single bonds. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, and biphenylenyl.
The term xe2x80x9csubstituted arylxe2x80x9d refers to aryl groups as defined above having one or more substituents independently selected from cyano, halo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkyl, fluorinated C1-C6 alkoxy, aryl and the like.
The term xe2x80x9cheterocyclexe2x80x9d (which may alternatively be referred to as xe2x80x9cheterocyclicxe2x80x9d) broadly refers to a 4- to 8-membered monocyclic ring or 7- to 10-membered bicyclic ring system, any ring of which is saturated or unsaturated, and which consists of carbon atoms and one or more heteroatoms selected from N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heterocyclic ring may be attached at any heteroatom or carbon atom, provided that attachment results in the creation of a stable structure. It is understood that xe2x80x9cunsaturatedxe2x80x9d means that the ring or rings may be partially or completely unsaturated. Representative examples of heterocyclics include piperidinyl, piperazinyl, azepinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, imidazolinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinoxazolinyl, isothiazolidinyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadazolyl, benzopyranyl, benzothiazolyl, benzoazolyl, furyl, tetrahydrofuryl, tetrahydropuranyl, thienyl (also referred to as thiophenyl), benzothiophenyl, oxadiazolyl, and furopyridyl.
The term xe2x80x9csubstituted heterocyclexe2x80x9d (alternatively xe2x80x9csubstituted heterocyclicxe2x80x9d) refers to a heterocycle as defined above having one or more substituents independently selected from cyano, halo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkyl, fluorinated C1-C6 alkoxy, aryl and the like.
The term xe2x80x9csubstitutedxe2x80x9d includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution is chemically allowed and results in a chemically stable compound.
When any variable or term occurs more than one time in any constituent or in Formula (I), its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if R2 and R3 are both designated as xe2x80x9cC1-C4 alkylxe2x80x9d, R2 and R3 can represent the same or different alkyl groups embraced by the term.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The present invention includes pharmaceutical compositions useful for inhibiting HIV protease, comprising an effective amount of a compound of this invention, and a pharmaceutically acceptable carrier. Pharmaceutical compositions useful for treating infection by HIV, or for treating AIDS or ARC, are also encompassed by the present invention, as well as a method of inhibiting HIV protease, and a method of treating infection by HIV, or of treating AIDS or ARC. Additionally, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of an HIV infection/AIDS treatment agent selected from:
(1) an HIV/AIDS antiviral agent,
(2) an anti-infective agent, and
(3) an immunomodulator.
The present invention also includes the use of a compound of the present invention as described above in the preparation of a medicament for (a) inhibiting HIV protease, (b) preventing or treating infection by HIV, or (c) treating AIDS or ARC.
The present invention further includes the use of any of the HIV protease inhibiting compounds of the present invention as described above in combination with one or more HIV infection/AIDS treatment agents selected from an HIV/AIDS antiviral agent, an anti-infective agent, and an immunomodulator for the manufacture of a medicament for (a) inhibiting HIV protease, (b) preventing or treating infection by HIV, or (c) treating AIDS or ARC, said medicament comprising an effective amount of the HIV protease inhibitor compound and an effective amount of the one or more treatment agents.
The compounds of the present invention may have asymmetric centers and may occur, except when specifically noted, as mixtures of stereoisomers or as individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention.
The compounds of the present invention in a therapeutically effective amount are useful in the inhibition of HIV protease, the prevention or treatment of infection by human immunodeficiency virus (HIV) and the treatment of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HIV is defined as including, but to limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by e.g., blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery. The compounds of the invention can also be used in xe2x80x9csalvagexe2x80x9d therapy; i.e., the compounds can be used to treat HIV infection, AIDS, or ARC in HIV-positive subject whose viral load achieved undetectable levels via conventional therapies employing known protease inhibitors, and then rebounded due to the emergence of HIV mutants resistant to the known inhibitors.
The compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV protease, e.g., by competitive inhibition, Thus the compounds of this invention are commercial products to be sold for these purposes.
The present invention also provides for the use of a compound of structural Formula (I) to make a pharmaceutical composition useful for inhibiting HIV protease and in the treatment of AIDS or ARC.
The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to all acceptable salts of the compounds of Formula (I) (in the form of water- or oil-soluble or dispersible products) and includes the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of acid addition salts include acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as ethylenediamine, N-methyl-glutamine, N,Nxe2x80x2-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, choline, N-benzylphenethyl-amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and dicyclohexylamine, and salts with amino acids such as arginine, lysine, ornithine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates such as dimethyl, diethyl, dipropyl, dibutyl, and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides, and iodides; and aralkyl halides such as benzyl and phenethyl bromides and others. The salt can be used as a dosage form for modifying the solubility or hydolysis characteristics of the compound or can be used in sustained release or pro-drug formulations.
Also, pharmaceutically acceptable esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
For these purposes, the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intraveneous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
The term xe2x80x9cadministrationxe2x80x9d and variants thereof (e.g., xe2x80x9cadministeringxe2x80x9d a compound) in reference to a compound of the invention each mean providing the compound or a prodrug of the compound to the individual in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., HIV/AIDS antivirals), xe2x80x9cadministrationxe2x80x9d and its variants are each understood to include concurrent and sequential provision of the compound or prodrug thereof and other agents.
Thus, in accordance with the present invention there is further provided a method of treating and a pharmaceutical composition for treating HIV infection and AIDS. The treatment involves administering to a subject in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically-effective amount of a compound of the present invention.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specific amounts.
By xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The term xe2x80x9csubject,xe2x80x9d (alternatively referred to herein as xe2x80x9cpatientxe2x80x9d) as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
These pharmaceutical compositions may be in the form of orally-administrable suspensions or tablets, nasal sprays, sterile injectible preparations, for example, as sterile injectible aqueous or oleagenous suspensions or suppositories.
When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
When administered by nasal aerosol inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
The injectible solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer""s solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
The compounds of this invention can be administered orally to humans in a dosage range of 0.01 to 1000 mg/kg body weight in divided doses. One preferred dosage range is 0.1 to 200 mg/kg body weight orally in divided doses. Another preferred dosage range is 0.5 to 100 mg/kg body weight orally in divided doses. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
The present invention is also directed to combinations of the HIV protease inhibitor compounds with one or more agents useful in the treatment of HIV infection and AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the HIV/AIDS antivirals, imunomodulators, antiinfectives, or vaccines, such as those in Table 1 as follows:
It will be understood that the scope of combinations of the compounds of this invention will HIV/AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in Table 1 above, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
One preferred combination is a compound of the present invention and a nucleoside inhibitor of HIV reverse transcriptase such as AZT, 3TC, ddC, or ddI. Another preferred combination is a compound of the present invention and a non-nucleoside inhibitor of HIV reverse transcriptase, such as efavirenz, and optionally a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. Still another preferred combination is any one of the foregoing combinations further comprising an additional HIV protese inhibitor such as indinavir, Compound A, nelfinavir, ritonavir, saquinavir, amprenavir, or abacavir. A preferred additional inhibitor of HIV protease is the sulfate salt of indinavir. Other preferred additional protease inhibitors are nelfinavir and ritonavir. Still another preferred additional inhibitor of HIV protease is saquinavir which is administered in a dosage of 600 or 1200 mg tid.
Other preferred combinations include a compound of the present invention with the following (1) efavirenz, optionally with AZT and/or 3TC and/or ddI and/or ddC, and optionally with indinavir; (2) any of AZT and/or ddI and/or ddC and/or 3TC, and optionally with indinavir; (3) d4T and 3TC and/or AZT; (4) AZT and 3TC; and (5) AZT and d4T.
In such combinations the compound of the present invention and other active agents may be administered together or separately. In addition, the administration of one agent may be prior to, concurrent to, or subsequent to the administration of other agent(s). These combinations may have unexpected effects on limiting the spread and degree of infection of HIV.
Efavirenz is (xe2x88x92)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, also known as DMP-266 or SUSTIVA(copyright) (DuPont) or STOCRIN(copyright) (Merck). Efavirenz and its utility as an HIV reverse transcriptase inhibitor is described in U.S. Pat. No. 5,519,021 and in the corresponding PCT published application, WO 95/20389. Efavirenz can be synthesized by the protocol of U.S. Pat. No. 5,633,405. Additionally, the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition and cyclization sequence is described in Thompson et al., Tetrahedron Letters 1995, 36: 8937-40, as well as in the PCT publication, WO 96/37457.
AZT is 3xe2x80x2-azido-3xe2x80x2-deoxythymidine, is also known as zidovudine, and is available from Burroughs-Wellcome under the tradename RETROVIR(copyright). Stavudine is 2xe2x80x2,3xe2x80x2-didehydro-3xe2x80x2-deoxythymidine, is also known as 2xe2x80x2,3xe2x80x2-dihydro-3xe2x80x2-deoxythymidine and d3T, and is available from Bristol-Myers Squibb under the tradename ZERIT(copyright). 3TC is (2R-cis)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone, is also known as (xe2x88x92)-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine and lamivudine, and is available from Glaxo Wellcome under the tradename EPIVIR(copyright). ddC is 2xe2x80x2,3xe2x80x2-dideoxycytidine, is also known as zalcitabine, and is available from Hoffman LaRoche under the tradename HIVID(copyright). ddI is 2xe2x80x2,3xe2x80x2-dideoxyinosine, is also known as didanosine, and is available from Bristol-Myers-Squibb under the tradename VIDEX(copyright). The preparation of ddC, ddI and AZT are also described in EPO 0,484,071.
Indinavir is N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-Nxe2x80x2-(t-butylcarboxamido)-piperazinyl))-pentaneamide, and can be prepared as described in U.S. Pat. No. 5,413,999. Indinavir is generally administered as the sulfate salt at a dosage of 800 mg three times a day. Indinavir is available from Merck under the tradename CRIXIVAN(copyright).
Compound A is N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(2-benzo [b]furanylmethyl)-2(S)-Nxe2x80x2-(t-butylcarboxamido)-piperazinyl)) pentaneamide, preferably administered as the sulfate salt. Compound A can be prepared as described in U.S. Pat. No. 5,646,148.
Ritonavir is [5S-(5R*,8R*,10R*,11R*)]-10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis (phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid 5-thiazolylmethyl ester, also known as 5-thiazolylmethyl [(aS)-a-[(1S,3S)-1-hydroxy-3-[(2S)-2-[3-[(2-isopropyl-4-thiazolyl) methyl]-3-methylureido]-3-methylbutyramido]-4-phenylbutyl]phenethyl]carbamate. It is available from Abbott under the tradename NORVIR(copyright). Ritonavir can be prepared as described in U.S. Pat. No. 5,484,801.
Nelfinavir is [3S-[2(2S*,3S*),3a,4ab,8ab]]-N-(1,1-dimethylethyl) decahydro-2-[2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl) amino]-4-(phenylthio)butyl]-3-isoquinolinecarboxamide monomethanesulfonate and VIRACEPT(copyright), which is commercially available from Agouron. Nelfinavir can be prepared as described in U.S. Pat. No. 5,484,926.
Saquinavir is N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide, also known as INVIRASE(copyright). Saquinavir can be prepared in accordance with procedures disclosed in U.S. Pat. No. 5,196,438. INVIRASE(copyright) (saquinavir mesylate) is available from Roche Laboratories. Saquinavir can be prepared as described in U.S. Pat. No. 5,196,438.
Amprenavir is 4-amino-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide, also known as Compound 168 W94. Amprenavir is an aspartyl protease inhibitor that can be prepared by following the procedures described in U.S. Pat. No. 5,585,397. Amprenavir is available under the tradename AGENERASE(copyright) from Glaxo Wellcome. Amprenavir can be prepared as described in U.S. Pat. No. 5,783,701.
Abacavir is (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol, also known as 1592U89. Abacavir can be prepared by following the protocol of EP 0434450.
Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows:
AcOH=acetic acid
AIB=aminoisobutyric acid
BOC or Boc=t-butyloxycarbonyl
CBZ=carbobenzoxy (alternatively, benzyloxycarbonyl)
DAST=(diethylamino)sulfur trifluoride
DCM=dichloromethane
DIEA=diisopropylethylamine
DME=dimethoxyethane
DMF=dimethylformamide
DMSO=dimethyl sulfoxide
EDC=1-ethyl-3-(3-dimethylaminoproyl) carbodiimide
EtOAc=ethyl acetate
HBTU=1-hydroxybenzotriazole
HOAT=1-hydroxy-7-azabensotriazole
HOBT=1-hydroxy benzotriazole hydrate
LC=liquid chromatography
LDA=lithium diisopropyl amide
mCPBA=meta-chloroperbenzoic acid
MS=mass spectrometry
NMR=nuclear magnetic resonance
Ph=phenyl
TBAF=tetrabutylammonium fluoride
TBSCI=t-butyldimethylsilyl chloride
TFA=trifluoroacetic acid
THF=tetrahydrofuran
TLC=thin layer chromatography
The compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicates, all variables are as defined above.
The preparation of the compounds of the present invention can be carried out in sequential or convergent synthetic routes, as shown in Schemes 1-6 below. A compound of Formula (I) can be prepared in accordance with Scheme 1, wherein Compound 1 is readily prepared via literature procedures described in Dorsey et al., J. Med. Chem. 1994, 37:3443-3451, and also in U.S. Pat. No. 5,413.999. Oxidation of compound 1 to acid 2 can be carried out by a number of methods known to those skilled in the art including oxidation with chromium trioxide in acetic acid. Amide coupling of compound 2 with an amine such as 3 is typically performed by the carbodiimide method with reagents such as EDC and HOBT in an inert solvent such as dichloromethane. Other methods of forming the amide or peptide bond include, but are not limited to, the synthetic routes via an acid chloride, azide, mixed anhydride or activated ester. Compound 4 is then hydrolyzed with aqueous lithium hydroxide and the resulting hydroxy acid 5 is conveniently protected with a standard silyl protecting group such as t-butyldimethyl silyl by reaction with either 5-butyldimethylsilyl chloride in the presence of imidazole in an inert solvent or the reaction with the silyl triflate and diisopropyl ethylamine again in an inert solvent such as dichloromethane. Mild aqueous hydrolysis of the silyl ester provides the protected hydroxy-acid 6 which is then coupled to NH2R5 using standard amide coupling reactions as described above to produce compound 7. The protecting group is removed with fluoride to arrive at compound 8.
As shown in Scheme 2, compounds of the invention of Formula (II) can be prepared in accordance with Scheme 1 by substituting the appropriate amine 9 for 3 in the amide coupling reaction with acid 2 to produce compound 10, which is then carried on to the desired compound 11.
Intermediate compounds 3 can be produced by coupling a suitably protected amino acid such as 12 to an amine NHR6R7 using known amide coupling procedures as shown in Scheme 3 to produce 13. Removal of the protecting group then provides 3 which is ready for amide coupling. The desired protected amino acid derivatives are, in many cases, commercially available where the protecting group L is, for example, a BOC or CBZ group. Other suitably protected natural and unnatural amino acids can be prepared by literature methods including classical methods familiar to those skilled in the art, including Williams, Synthesis of Optically Active xcex1-Amino Acids, 17, Pergamon Press, Oxford, 1989; and Williams, Aldrichimica Acta 1992, 25: 11-25.
Boc protecting groups can be removed by treatment with strong acids such as trifluoroacetic acid in dichloromethane or HCl in methanol. CBZ groups are readily removed by hydrogenolysis with a palladium catalyst under a hydrogen atmosphere in an alcoholic solvent such as methanol or ethanol. Removal of the protecting group can also be accomplished by a number of methods known in the art, such as those described in Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991.
Chemical modifications of known amino acids provides another source of amines for coupling to acid 2 as exemplified by 4-hydroxyproline in Scheme 4. Amide coupling of NHR6R7 to 4-hydroxyproline as above provides 15. The chloro and fluoro compounds are available by treatment of 15 with CCl4/PPh3 or DAST as reported in Bioorganic and Medicinal Chemistry 1996, 4: 1365-1377. Acid removal of the BOC protecting group then provides 17 which can be elaborated to the compounds of interest according to the synthetic route described in Scheme 1.
Intermediates of formula NH2R5 can be readily prepared via procedures set forth in the literature including, but not limited to, those found in Tetrahedron Letters 1991, 32: 711-714, Tetrahedron Letters 1995, 36: 3993-3996 and Synthesis 1998, 938-961.
A sequential synthetic route to the compounds of the invention is shown in Scheme 5. An amino acid allyl ester can be coupled to acid 2 using standard amide coupling chemistry as described above in Scheme 1. Removal of the allyl group is accomplished with a palladium catalyst in the presence of dimethylbarbituric acid and the resulting acid 20 can then be coupled to NHR6R7 to provide lactone 4.
Another method for preparing intermediate 1 of the invention is shown in Scheme 6. Compound 21 can be prepared according to known procedures including those described in Tetrahedron Letters 1995, 36: 2195-2198. Iodolactonization of 21 provides 22 which is then converted into 1 by treatment with silver trifluoroacetate followed by base hydrolysis with sodium carbonate in methanol. Compound 1 is then elaborated to the compounds of interest as shown in Scheme 1.

Alpha-hydroxy-gamma-[[(carbocyclic-or heterocyclic-substituted)amino]carbonyl]alkanamide derivatives and uses thereof


This is an improved method of fabricating Zircaloy-4 strip. The method is of the type wherein Zircaloy-4 material is vacuum melted, forged, hot reduced, beta-annealed, quenched, hot rolled, subjected to a post-hot-roll anneal and then reduced by at least two cold rolling steps, including a final cold rolling to final size, with intermediate annealing between the cold rolling steps and with a final anneal after the last cold rolling step. The improvement comprises: (a) utilizing a maximum processing temperature of 620.degree. C. between the quenching and the final cold rolling to final size; (b) utilizing a maximum intermediate annealing temperature of 520.degree. C.; and (c) utilizing hot rolling, post-hot-roll annealing, intermediate annealing and final annealing time-temperature combinations to give an A parameter of between 4.times.10.sup.-19 and 7.times.10.sup.-18 hour, where segment parameters are calculated for the hot rolling step and each annealing step, the segment parameters are calculated by taking the time, in hours, for which that step is performed, to the (-40,000/T) power, in which T is the temperature, in degrees K, at which the step is performed, and where the A parameter is the sum of the segment parameters. Preferably, the hot rolling and the post-hot-roll anneal are at 560.degree.-620.degree. C. and are for 1.5-3 hours and the intermediate annealing is at 400.degree.-520.degree. C. and is for 1.5-15 hours and the final anneal after the last cold rolling step is at 560.degree.-710.degree. C. for 1-5 hours, and the beta-anneal is at 1015.degree.-1130.degree. C. for 2-30 minutes.

The invention relates to a zirconium based material and more particularly to methods for improved corrosion resistance of Zircaloy-4 strip material (as opposed to other alloys or to Zircaloy-4 tubing).
In the development of nuclear reactors, such as pressurized water reactors and boiling water reactors, fuel designs impose significantly increased demands on all of the core strip and tubular cladding (strip is used for grids, guide tubes, and the like). The corrosion of strip is somewhat different from that of cladding as the two have quite different texture (strip is rolled, while cladding is pilgered). Such components are conventionally fabricated from the zirconium-based alloys, Zircaloy-2 and Zircaloy-4. Increased demands on such components will be in the form of longer required residence times and thinner structural members, both of which cause potential corrosion and/or hydriding problems.
Commercial reactors generally use either Zircaloy-2 or Zircaloy-4, (see U.S. Pat. Nos. 2,772,964 and 3,148,055). Zircaloy-2 is a zirconium alloy having about 1.2-1.7 weight percent (all percents herein are weight percent) tin, 0.07-0.20 percent iron, about 0.05-0.15 percent chromium, and about 0.03-0.08 percent nickel. Zircaloy-4 contains about 1.2-1.7 percent tin, about 0.18-0.24 percent iron, and about 0.07-0.13 percent chromium.
Fabrication schedules for Zircaloy-4 have been developed with regard to corrosion resistance. Generally, different processing methods result in either good uniform or good nodular corrosion resistance but not both. The effect of thermal treatment variations has been accounted for by the cumulative A-parameter (see Steinberg, et al. "Zirconium in the Nuclear Industry: Sixth International Symposium, ASTM STP 824, American Society for Testing and Materials, Philadelphia, 1984). Charquet, et al. (see D. Charquet, et al. "Influence of Variations in Early Fabrication Steps on Corrosion, Mechanical Properties and Structures of Zircaloy-4 Products", Zirconium in the Nuclear Industry: Seventh International Symposium, ASTM, STP 939, ASTM, 1987, pp. 431-447) investigated the effects of early stage tube processing on uniform (400.degree. C.) and nodular (500.degree. C.) corrosion. Charquet's results showed that, with increasing cumulative A-parameter, nodular corrosion increases, but that uniform corrosion decreases.

Zircaloy-4 processing for uniform and nodular corrosion resistance


A station for compliance testing of unmanned vehicles comprises a dedicated area for acceptance of an unmanned vehicle. The dedicated area is configured for permitting the unmanned vehicle to be in a first inspection position. The station further comprises a transmitter. The transmitter is directed towards the dedicated area. The transmitter is configured to instruct the unmanned vehicle to perform a behavior. The station further comprises a sensor. The sensor is directed towards the dedicated area. The sensor is configured to detect a non-compliance of the unmanned vehicle. The detected non-compliance is in response to the instructed performed behavior of the unmanned vehicle.

The present disclosure relates to unmanned entities (alternatively, drones), and more specifically, to the inspection, verification, and self-verification of drones for compliance based on observed drone operation.
Drones operate in many use cases and situations. Drones may be used in construction and cartography, such as providing aerial additional viewpoints of buildings and the exploration of various natural terrains. Drones may be used in safety and rescue, such as extending the reach of supplies and communications to remote or hazardous areas. Drones may be used in commercial or retail industries, such as the delivery of packages. Drones may be used in agricultural endeavors, such as the care and inspection of crops.

Non-intrusive unmanned entity inspection

International Business Machines Corporation


A fuel tank mounting and protective cage for vehicles such as school buses including side structures and a bottom shelf structure, each of these structures being weldments constructed of low carbon, high strength steel tubing having rectangular cross-sections. The bottom structure is connected to the side structures by bolt assemblies, preferably disposed in laterally offset parallel rows, to produce stiff joints between the sections with the result that there is less rotation and localized deformation of the protection cage in the event of an accident. Hold down devices are carried by the bottom shelf structure for securing the fuel tank directly to the bottom shelf structure so that the bottom shelf and fuel tank may be removed as a unit for service.

The present invention relates generally to a mounting and protective cage for a fuel tank that is mounted between the side members of a vehicle such as a school bus.
An objective of this invention is to provide a vehicle, such as a school bus, with a large fuel tank, in the 100 gallon capacity range, that will be protected in the event of a crash, even at impact speeds of up to 30 mph from any direction, and otherwise meet Section 301 of the Federal Motor Vehicle Safety Standards. The fuel tank mounting and protective cage of this invention is intended to provide this degree of protection for any of the several combinations of suspension systems and tires that may be offered by the manufacturer of the vehicle chassis.
The side members or frames of vehicles, such as school buses, are constructed of substantial C-shaped steel beams. The area between these C-shaped steel beams or side members is thus well protected. Much of this protected area is already occupied by the exhaust system, the drive to the rear axle and the brake lines. However, a portion of this protected area rearward of the rear axle is available to receive a fuel tank.
The vehicle floor extends across the top flange of the side members and thus the fuel tank can not extend above the side members. Thus, to accommodate a 100 gallon fuel tank rearward of the rear axle, the tank must extend below the lower flange of the side members. However, there are limits to the distance below the side members and the distance to the rear of the vehicle that the fuel tank and its protective cage can extend.
The angle between the ground line and a line extending from the ground/tire interface of a rear tire and the lower edge of the rear bumper is called the departure angle. Nothing should extend down from the underside of the vehicle that violates the plane of this departure angle. Stated in another way, when the front wheels of a vehicle encounter an incline and the rear bumper moves toward the pavement, the rear bumper should scrape the pavement before anything else that extends down from the underside of the vehicle. Thus, the location of the bottom rear lateral edge of the mounting and protective cage is limited by the angle of departure.
The ease of assembly of the protective cage to the vehicle chassis and removal from the chassis for service are important attributes of this invention. Since the areas outwardly of the side members may be used for luggage compartments, the outer surfaces of the side members become inaccessible after installing the bus body and luggage compartments. Thus, removing the fuel tank for service must be possible without access to the bolts or other connecting devices that are located on the outer surfaces of the side members.
FIG. 1 illustrates a prior art mounting and protective cage for a fuel tank 10 that is mounted between the side members 12. It is apparent from FIG. 1 that, if this prior art device is struck with sufficient force at the location indicated by the arrow A in this view, the sheet metal liners 14 will bend causing the fuel tank 10 to shift and collide with the mounting and protective cage. The steel beams 28 that connect the lower edges of the liners 14 and extend laterally under the fuel tank 10 and the end plate 18 may shift, as a parallelogram, in the event of a side crash. This parallelogram type movement is permitted because the joint between the sheet metal liners 14 and the steel beams 28 has very little resistance to bending. This joint is formed by a bend 15 in the sheet metal liners 14 which can be bent in either direction. Thus, this prior art protective cage may be vulnerable in situations in which a side crash impacts below the lower flange of the side members.
For the foregoing reasons, there is a need for a fuel tank protective cage for mounting a fuel tank of the type that extends between and below the vehicle side members that protects the fuel tank from crashes that impact the protective cage below the lower flanges of the vehicle side members.

Protective cage for fuel tank installed between vehicle side members

Navistar International Transporation Corp.


A multilayered LED structure which has an active light-emitting layer of porous silicon carbide and a sequence of layers of porous silicon carbide underneath which serves as a quarter-wavelength multilayer mirror. The result is the electroluminescent emission of spectrally narrow visible light in the deep blue to UV range, in a highly directed pattern. The deep, intense blue luminescence is accomplished via the appropriate preparation and passivation of a single porous silicon carbide layer, followed by the deposition of a transparent, semiconducting layer, such as ITO (In.sub.2 O.sub.3) or ZnO.

Quantum mechanics dictates that electrons making transitions between allowed energy levels gain or lose a specific quanta of energy. In particular, the transition of an electron to an excited state is associated with the absorption of a quanta of energy and the transition of an electron to a state of lower energy produces a quanta of energy. In the latter case in which electrons make downward transitions to a lower energy level, energy is released in the form of both crystal lattice vibrations, i.e., phonons, and emitted light photons. The lattice vibrations are manifested as heat, while the photons are observable as light energy, which, if in the visible spectrum and of sufficient intensity, can be detected by the human eye.
Light emitting diodes (LEDs) are well known semiconductor devices which convert electrical energy into emitted light. In a LED, the generation or injection of a current across the LED's diode junction followed by the recombination of the injected carriers encourages such electronic transitions and their resulting productions of vibrational energy or light, or both.
In these electronic transitions, it is well known that the wavelength of the light produced is controlled by the energy difference of the electronic transition. Accordingly, smaller electronic transitions within the visible spectrum, tend to emit longer wavelengths of light toward the red portion of the visible spectrum, and larger energy transitions tend to emit shorter wavelengths of light toward the violet portion of the visible spectrum. Such transitions are used to characterize the materials in which they occur, thereby enabling materials to be identified by the specific manner in which they behave under incident electromagnetic radiation, including visible, ultraviolet and infrared light. Hence, the peak wavelengths and associated colors of the luminescence generated by a given type of semiconductor material are restricted to a select few. For various physical and technological reasons, it has been more difficult to produce LEDs which emit shorter wavelengths of light toward the violet portion of the spectrum, including blue LEDs.
Since blue is one of the primary colors, the limited availability of inexpensive efficient blue LEDs creates limitations in related technological fields.
It is known that, theoretically, blue light can be produced by any semiconductor material having a band gap of at least .about.2.5 electron volts (eV). The band gap of a given semiconductor material is the energy difference between the conduction band and the valence band of the semiconductor materials. Consequently, blue light emitting semiconductor diodes must be formed from a relatively large band gap semiconductor material such as gallium nitride (GaN), zinc selenide (ZnSe) or alpha silicon carbide (.alpha.-SiC).
The blue light produced by some of these semiconductor materials can be made more intense and more efficiently, by making the semiconductor material porous using well known anodizing and photoanodizing techniques. Some porous semiconductor materials exhibit unique optical properties which their bulk semiconductor counterparts can not equal. An example of this superiority is found in porous SiC which has exceptional optical and unique electronic properties due to its geometry. More specifically, porous SiC exhibits visible transparency and intense blue photoluminescence and electroluminescence. In terms of developing optoelectronic devices from porous semiconductor materials, some progress has been made in developing porous Si-based light emitting devices. Since the oxidation rates of bulk SiC and porous SiC are much lower than that of bulk Si and porous Si, and since SiC has been identified as a material for use at high temperatures, optoelectronic devices based on porous SiC will be much more stable over longer periods of time, and also at higher temperatures than those based on porous Si.
Another unique optical property of porous semiconductor materials, one which is employed in the current innovation, is that the porous semiconductor layer can be prepared so that its optical index of refraction varies spatially, in a periodic or continuously varying manner, or otherwise, due to a change in its porosity. With this, such a structure can function as an optical waveguide or optical interference filter.
Films of SiC are made porous by electrochemically fabricating a microcrystalline porous structure from bulk SiC with pore spacings of "quantum" dimensions (less than 10 nm). The resulting porous structure provides a large internal surface. The porous structure can be fabricated using either dark-current or light-assisted electrochemical means as disclosed in U.S. Pat. No. 5,376,241 entitled FABRICATING POROUS SILICON CARBIDE and U.S. Pat. No. 5,454,915 entitled METHOD OF FABRICATING POROUS SILICON CARBIDE (SIC), both of which were issued to Joseph S. Shor and Anthony D. Kurtz on Oct. 3, 1995 and assigned to Kulite Semiconductor Products, Inc., the assignee herein. Using these techniques to make films of SiC porous, it is possible to increase the quantum efficiency of SiC, resulting in UV or deep blue luminescence. Such porous SiC films exhibit a spectrally integrated photoluminescence intensity (and efficiency) which is approximately twenty (20) times higher than that which is observed from bulk Si, as discussed in Jonathan E. Spanier, et al., "Effects of Nanocrystalline Structure and Passivation on the Photoluminescent Properties of Porous Silicon Carbide", Mat. Res. Soc. Symp. Proc. Vol 452, pp 491-496, (1997). Accordingly, devices fabricated from porous SiC using existing processing techniques such as those described in U.S. Pat. Nos. 5,376,241 and 5,454,915, enable the development of semiconductor UV and blue light source and UV/blue optoelectronic devices.
The luminescence in the blue range of the spectrum can be further enhanced by passivating porous SiC with a passivation agent such as oxygen or hydrogen. Passivation enables the microcrystalline structures to satisfy the conditions for quantum confinement by preventing surface recombination at the dangling bond. Passivating agents that may be employed for this purpose include atomic hydrogen, deposited by a plasma or by an HF dip, oxygen, formed by thermal oxidation, anodically, or PECVD (plasma enhanced chemical vapor deposition) of oxygen, or any other passivating agent which will complete the dangling bond sites.
Initial demonstrations of room temperature luminescence from porous semiconductor materials such as porous SiC, created mush speculation about the mechanisms which provide visible luminescence. However, it is now generally agreed, based on considerable theoretical and experimental evidence, that, in some cases, at least a portion of the enhancement of the luminescence is associated with the scale of the quantum structures in the porous semiconductor material. These quantum structures may allow a relaxation of the momentum selection rules by confining the charge carriers spatially, thus allowing direct band-gap transitions. Additionally, it has been demonstrated in porous silicon that the quantum confinement of charge carriers increases the effective band-gap, thereby pushing it into the visible region.
It is also generally agreed that the surface chemistry in porous semiconductor materials plays an important role in luminescence. This suggests that luminescence in passivated porous semiconductor materials may have similar mechanisms as in bulk semiconductor materials like Si, which exhibit band-gap widening into the visible region when hydride species are formed on the surface. A portion of the visible luminescence of porous Si, for example, may be associated with silicon hydride (SiH). It is not positively known whether the hydrogen termination serves only to passivate the surface or whether there is a contribution to the luminescence by amorphous SiH. Nevertheless, it is very clear that silicon microcrystals having dimensions of less than 5 nm, exhibit band-gap widening and the above-described band-gap luminescence.
Accordingly, there is a need for an improved LED structure and method for making which exhibits electroluminescent emission in the deep blue portion of the visible spectrum.

Vertical cavity-emitting porous silicon carbide light-emitting diode device and preparation thereof