The present invention is directed to compounds of the formula I:

Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall, Cytokine, 3, 165-183 (1991) and Murphy, Rev. Immun. 12, 593-633 (1994)). There are two classes of chemokines, Cxe2x80x94Xxe2x80x94C (xcex1) and Cxe2x80x94C (xcex2), depending on whether the first two cysteines are separated by a single amino acid (Cxe2x80x94Xxe2x80x94C) or are adjacent (Cxe2x80x94C). The xcex1-chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils, whereas xcex2-chemokines, such as RANTES, MIP-1xcex1, MIP-1xcex2, monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, et al., Nature, 381, 661-666 (1996)).
The chemokines bind specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which are termed xe2x80x9cchemokine receptors.xe2x80x9d On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration. There are at least sixteen human chemokine receptors that bind or respond to xcex2-chemokines with the following characteristic pattern: CCR-1 (or xe2x80x9cCKR-1xe2x80x9d or xe2x80x9cCC-CKR-1xe2x80x9d) [MIP-1xcex1, MIP-1xcex2, MCP-3, RANTES] (Ben-Barruch, et al., J. Biol. Chem., 270, 22123-22128 (1995); Beote, et al, Cell, 72, 415-425 (1993)); CCR-2A and CCR-2B (or xe2x80x9cCKR-2Axe2x80x9d/xe2x80x9cCKR-2Axe2x80x9d or xe2x80x9cCC-CKR-2Axe2x80x9d/xe2x80x9cCC-CKR-2Axe2x80x9d) [MCP-1, MCP-3, MCP-4]; CCR-3 (or xe2x80x9cCKR-3xe2x80x9d or xe2x80x9cCC-CKR-3xe2x80x9d) [eotaxin, RANTES, MCP-3] (Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995); CCR-4 (or xe2x80x9cCKR-4xe2x80x9d or xe2x80x9cCC-CKR-4xe2x80x9d) [MIP-1xcex1, RANTES, MCP-1] (Power, et al., J. Biol. Chem., 270, 19495-19500 (1995)); CCR-5 (or xe2x80x9cCKR-5xe2x80x9d or xe2x80x9cCC-CKR-5xe2x80x9d) [MIP-1xcex1, RANTES, MIP-1xcex2] (Sanson, et al., Biochemistry, 35, 3362-3367 (1996)); and the Duffy blood-group antigen [RANTES, MCP-1] (Chaudhun, et al., J. Biol. Chem., 269, 7835-7838 (1994)). The xcex2-chemokines include eotaxin, MIP (xe2x80x9cmacrophage inflammatory proteinxe2x80x9d), MCP (xe2x80x9cmonocyte chemoattractant proteinxe2x80x9d) and RANTES (xe2x80x9cregulation-upon-activation, normal T expressed and secretedxe2x80x9d).
Chemokine receptors, such as CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR-4, have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma, rhinitis and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. A review of the role of chemokines in allergic inflammation is provided by Kita, H., et al., J. Exp. Med. 183, 2421-2426 (1996). Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases. Compounds which modulate chemokine receptors would be especially useful in the treatment and prevention of atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and particularly bronchial asthma.
A retrovirus designated human immunodeficiency virus (HIV-1) is the etiological agent of the complex disease that includes progressive destruction 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.
Certain compounds have been demonstrated to inhibit the replication of HIV, including soluble CD4 protein and synthetic derivatives (Smith, et al., Science, 238, 1704-1707 (1987)), dextran sulfate, the dyes Direct Yellow 50, Evans Blue, and certain azo dyes (U.S. Pat. No. 5,468,469). Some of these antiviral agents have been shown to act by blocking the binding of gp120, the coat protein of HIV, to its target, the CD4 glycoprotein of the cell.
Entry of HIV-1 into a target cell requires cell-surface CD4 and additional host cell cofactors. Fusin has been identified as a cofactor required for infection with virus adapted for growth in transformed T-cells, however, fusin does not promote entry of macrophagetropic viruses which are believed to be the key pathogenic strains of HIV in vivo. It has recently been recognized that for efficient entry into target cells, human immunodeficiency viruses require a chemokine receptors, most probably CCR-5 or CXCR-4, as well as the primary receptor CD4 (Levy, N. Engl. J. Med., 335(20), 1528-1530 (Nov. 14, 1996). The principal cofactor for entry mediated by the envelope glycoproteins of primary macrophage-trophic strains of HIV-1 is CCR5, a receptor for the xcex2-chemokines RANTES, MIP-1xcex1 and MIP-1xcex2 (Deng, et al., Nature, 381, 661-666 (1996)). HIV attaches to the CD4 molecule on cells through a region of its envelope protein, gp120. It is believed that the CD-4 binding site on the gp120 of HIV interacts with the CD4 molecule on the cell surface, and undergoes conformational changes which allow it to bind to another cell-surface receptor, such as CCR5 and/or CXCR-4. This brings the viral envelope closer to the cell surface and allows interaction between gp41 on the viral envelope and a fusion domain on the cell surface, fusion with the cell membrane, and entry of the viral core into the cell. It has been shown that xcex2-chemokine ligands prevent HIV-1 from fusing with the cell (Dragic, et al., Nature, 381, 667-673 (1996)). It has further been demonstrated that a complex of gp120 and soluble CD4 interacts specifically with CCR-5 and inhibits the binding of the natural CCR-5 ligands MIP-1xcex1 and MIP-1xcex2 (Wu, et al., Nature, 384, 179-183 (1996); Trkola, et al., Nature, 384, 184-187 (1996)).
Humans who are homozygous for mutant CCR-5 receptors which do not serve as co-receptors for HIV-1 in vitro appear to be unusually resistant to HIV-1 infection and are not immuno-compromised by the presence of this genetic variant (Nature, 382, 722-725 (1996)). Absence of CCR-5 appears to confer substantial protection from HIV-1 infection (Nature, 382, 668-669 (1996)). Other chemokine receptors may be used by some strains of HIV-1 or may be favored by non-sexual routes of transmission. Although most HIV-1 isolates studied to date utilize CCR-5 or fusin, some can use both as well as the related CCR-2B and CCR-3 as co-receptors (Nature Medicine, 2(11), 1240-1243 (1996)). Nevertheless, drugs targeting chemokine receptors may not be unduly compromised by the genetic diversity of HIV-1 (Zhang, et al., Nature, 383, 768 (1996)). Accordingly, an agent which could block chemokine receptors in humans who possess normal chemokine receptors should prevent infection in healthy individuals and slow or halt viral progression in infected patients. By focusing on the host""s cellular immune response to HIV infection, better therapies towards all subtypes of HIV may be provided. These results indicate that inhibition of chemokine receptors presents a viable method for the prevention or treatment of infection by HIV and the prevention or treatment of AIDS.
The peptides eotaxin, RANTES, MIP-1xcex1, MIP-1xcex2, MCP-1, and MCP-3 are known to bind to chemokine receptors. As noted above, the inhibitors of HIV-1 replication present in supernatants of CD8+ T cells have been characterized as the xcex2-chemokines RANTES, MIP-1xcex1 and MIP-1xcex2.
The present invention is directed to compounds which inhibit the entry of human immunodeficiency virus (HIV) into target cells and are of value in the prevention of infection by HIV, the treatment of infection by HIV and the prevention and/or treatment of the resulting acquired immune deficiency syndrome (AIDS). The present invention also relates to pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other agents for the prevention and treatment of AIDS and viral infection by HIV.
The present invention is further directed to compounds which are modulators of chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which chemokine receptors are involved.
The present invention is directed to compounds of formula I:
wherein:
X is selected from:
xe2x80x94(CO)NR9xe2x80x94, xe2x80x94NR9(CO)xe2x80x94, xe2x80x94O(CO)NR9xe2x80x94, xe2x80x94NR9(CO)Oxe2x80x94, and xe2x80x94NR9(CO)NR10xe2x80x94,
where R9 is independently selected from: hydrogen, C1-10 alkyl, C3-8 cycloalkyl, C1-6 alkyl-C3-6 cycloalkyl, C2-10 alkenyl, C2-10 alkynyl, benzyl, phenyl, or naphthyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, C1-6 alkyl, C1-3 alkoxy, phenyl and trifluoromethyl,
and where R10 is independently selected from: hydrogen, C1-6 alkyl, benzyl, or phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl,
or where R9 and R10 may be joined together to form a 5-8 membered ring which may be unsubstituted or substituted with halo, C1-3 alkyl, and C1-3 alkoxy;
Y is selected from:
a single bond, xe2x80x94(CO)xe2x80x94, xe2x80x94(CO)Oxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94SO2NR9xe2x80x94, xe2x80x94C1-10 alkyl-, xe2x80x94(CO)NR9xe2x80x94, and xe2x80x94(CS)NR9xe2x80x94;
Z is selected from:
a single bond, xe2x80x94NR9xe2x80x94, xe2x80x94Oxe2x80x94, and xe2x80x94C1-10 alkyl-;
R1 is selected from:
phenyl, naphthyl, heterocycle other than tetrazolyl, C1-10 alkyl, C3-6 cycloalkyl, C1-6 alkyl-C3-6 cycloalkyl, C2-10 alkenyl, C2-10 alkynyl, C1-4 alkyl-phenyl or C1-4 alkyl-heterocycle, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, C1-3 alkyl, C1-3 alkoxy, trifluoromethoxy and trifluoromethyl,
or when Z is xe2x80x94NR9xe2x80x94, then R9 and R1 may be joined together to form a 5-8 membered alkyl or heterocycle ring which may be unsubstituted or substituted with halo, C1-3 alkyl, and C1-3 alkoxy;
R2 is selected from:
(1) hydrogen, and
(2) hydroxy, or R2 and Z may be joined together to form a double bond;
R3 is selected from the group consisting of:
phenyl and heterocycle, which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3 alkyl,
(e) xe2x80x94Oxe2x80x94C1-3 alkyl,
(f) xe2x80x94CO2R9,
(g) xe2x80x94NR9R10, and
(h) xe2x80x94CONR9R10;
R7 is selected from:
(1) hydrogen,
(2) C1-6 alkyl, which is unsubstituted or substituted with 1-4 substituents where the substituents are independently selected from: hydroxy, cyano, and halo,
(3) hydroxy, and
(4) halo;
R8 is selected from:
C1-10 alkyl, C3-6 cycloalkyl, C2-10 alkenyl, C2-10 alkynyl, phenyl, C1-6 alkyl-phenyl, C1-6 alkyl-C3-6 cycloalkyl,
xe2x80x83C1-4 alkyl-Oxe2x80x94C0-4 alkyl-phenyl, naphthyl, biphenyl, and heterocycle, which is unsubstituted or substituted with 1-7 of R12 where
xe2x80x83R12 is independently selected from:
(a) halo,
(b) cyano,
(c) hydroxy,
(d) C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R13 where R13 is independently selected from: halo, cyano, hydroxy, C1-6 alkoxy, xe2x80x94CO2H, xe2x80x94CO2(C1-6 alkyl), phenyl, trifluoromethyl, and xe2x80x94NR9R10,
(e) xe2x80x94Oxe2x80x94C1-6alkyl, which is unsubstituted or substituted with 1-5 of R13,
(f) xe2x80x94CF3,
(g) xe2x80x94CHF2,
(h) xe2x80x94CH2F,
(i) xe2x80x94NO2,
(j) phenyl,
(k) xe2x80x94CO2R9,
(l) tetrazolyl,
(m) xe2x80x94NR9R10,
(n) xe2x80x94NR9xe2x80x94COR10,
(o) xe2x80x94NR9xe2x80x94CO2R10,
(p) xe2x80x94COxe2x80x94NR9R10,
(q) xe2x80x94OCOxe2x80x94NR9R10,
(r) xe2x80x94NR9COxe2x80x94NR9R10,
(s) xe2x80x94S(O)mxe2x80x94R9, wherein m is an integer selected from 0, 1 and 2,
(t) xe2x80x94S(O)2xe2x80x94NR9R10,
(u) xe2x80x94NR9S(O)2xe2x80x94R10,
(v) xe2x80x94NR9S(O)2xe2x80x94NR9R10,
(w) 1-naphthyl, and
(x) 2-naphthyl;
x is an integer selected from 0, 1 and 2, and y is an integer selected from 0, 1 and 2, with the proviso that the sum of x and y is 2;
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
One embodiment of the present invention is a compound of formula I,
wherein
X is selected from:
xe2x80x94(CO)NR9xe2x80x94, xe2x80x94NR9(CO)xe2x80x94, xe2x80x94O(CO)NR9xe2x80x94, xe2x80x94NR9(CO)Oxe2x80x94, and xe2x80x94NR9(CO)NR10xe2x80x94,
where R9 is independently selected from: hydrogen, C1-10 alkyl, C3-8 cycloalkyl, C1-6 alkyl-C3-6 cycloalkyl, C2-10 alkenyl, C2-10 alkynyl, benzyl or phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, C1-6 alkyl, C1-3 alkoxy, phenyl and trifluoromethyl,
and where R10 is independently selected from: hydrogen, C1-6 alkyl, benzyl, or phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl,
or where R9 and R10 may be joined together to form a 5-8 membered ring which may be unsubstituted or substituted with halo, C1-3 alkyl, and C1-3 alkoxy;
Y is selected from:
a single bond, xe2x80x94(CO)xe2x80x94, xe2x80x94(CO)Oxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94C1-10 alkyl-, xe2x80x94(CO)NR9xe2x80x94, and xe2x80x94(CS)NR9xe2x80x94;
Z is selected from:
a single bond, xe2x80x94NR9xe2x80x94, xe2x80x94Oxe2x80x94, and xe2x80x94C1-10 alkyl-;
R1 is selected from:
phenyl, heterocycle other than tetrazolyl, C1-10 alkyl, C3-6 cycloalkyl, C1-6 alkyl-C3-6 cycloalkyl, C2-10 alkenyl, C2-10 alkynyl, C1-4 alkyl-phenyl or C1-4 alkyl-heterocycle, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, C1-3 alkyl, C1-3 alkoxy, trifluoromethoxy and trifluoromethyl,
or when Z is xe2x80x94NR9xe2x80x94, then R9 and R1 may be joined together to form a 5-8 membered alkyl or heterocycle ring which may be unsubstituted or substituted with halo, C1-3 alkyl, and C1-3 alkoxy;
and all other variables are as previously defined;
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
Another embodiment of the present invention is a compound of formula I, wherein Y is selected from a single bond, xe2x80x94(CO)xe2x80x94, xe2x80x94(CS)NR9xe2x80x94, xe2x80x94(CO)Oxe2x80x94, xe2x80x94SO2xe2x80x94, and xe2x80x94(CO)NR9xe2x80x94;
R9 is independently selected from hydrogen and C1-6 alkyl;
Z is selected from a single bond, xe2x80x94Oxe2x80x94, and xe2x80x94NR9xe2x80x94;
and all other variables are as defined in the preceding embodiment;
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
Preferred compounds of the present invention include those of formula Ia:
wherein R1, R3, R7, R8, X, Y and Z are defined herein;
and pharmaceutically acceptable salts and individual diastereomers thereof.
More preferred compounds of the present invention include those of formula Ic:
wherein R1, R3, R8, X, Y and Z are defined herein;
and pharmaceutically acceptable salts and individual diastereomers thereof.
Highly preferred compounds of the present invention include those of formula Id:
wherein R1, R8, X, Y and Z are defined herein;
and pharmaceutically acceptable salts and individual diastereomers thereof.
In the present invention it is preferred that X is selected from:
xe2x80x94(CO)NR9xe2x80x94, xe2x80x94NR9(CO)xe2x80x94, xe2x80x94NR9(CO)Oxe2x80x94, and xe2x80x94NR9(CO)NR10xe2x80x94,
where R9 is independently selected from: hydrogen, C1-10 alkyl, C3-6 cycloalkyl, C1-6 alkyl-C3-6 cycloalkyl, C2-10 alkenyl, C2-10 alkynyl, benzyl or phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl,
and where R10 is independently selected from: hydrogen, C1-6 alkyl, benzyl, or phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl,
or where R9 and R10 may be joined together to form a 5-8 membered ring which may be unsubstituted or substituted with halo, C1-3 alkyl, and C1-3 alkoxy;
In the present invention it is more preferred that X is selected from:
xe2x80x94NR9(CO)Oxe2x80x94 and xe2x80x94NR9(CO)NR10xe2x80x94,
where R9 is independently selected from: hydrogen, C1-10 alkyl, C2-10 alkenyl, and C1-6 alkyl-C3-6 cycloalkyl,
where R10 is independently selected from: hydrogen and C1-6 alkyl,
or where R9 and R10 may be joined together to form a 5-8 membered ring which is unsubstituted.
In the present invention it is even more preferred that X is selected from:
xe2x80x94NR9(CO)Oxe2x80x94 and xe2x80x94NR9(CO)NR10xe2x80x94,
where R9 is independently selected from: hydrogen, C1-10 alkyl, C2-10 alkenyl, and C1-6 alkyl-C3-6 cycloalkyl,
where R10 is independently selected from: hydrogen and C1-6 alkyl,
or where R9 and R10 may be joined together to form a 5-8 membered ring which is unsubstituted.
In the present invention it is still more preferred that X is selected from:
xe2x80x94NR9(CO)Oxe2x80x94, and xe2x80x94NR9(CO)NHxe2x80x94,
where R9 is independently selected from: methyl, ethyl, n-propyl, allyl, and xe2x80x94CH2-cyclopropyl.
In the present invention it is preferred that Y is selected from:
a single bond, xe2x80x94(CO)xe2x80x94, xe2x80x94(CS)NR9xe2x80x94, xe2x80x94(CO)Oxe2x80x94, xe2x80x94SO2xe2x80x94, and xe2x80x94(CO)NR9xe2x80x94,
where R9 is independently selected from hydrogen and C1-6 alkyl.
In the present invention it is more preferred that Y is selected from:
a single bond, xe2x80x94(CO)xe2x80x94, xe2x80x94(CS)NR9xe2x80x94, xe2x80x94(CO)Oxe2x80x94, xe2x80x94SO2xe2x80x94, and xe2x80x94(CO)NR9xe2x80x94,
where R9 is independently selected from hydrogen and methyl.
In the present invention it is preferred that Z is selected from:
a single bond, xe2x80x94Oxe2x80x94, and xe2x80x94NR9xe2x80x94,
where R9 is independently selected from hydrogen, C1-6 alkyl, C3-8 cycloalkyl, phenyl, and C1-6 alkyl-phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, C1-3 alkyl, C1-3 alkoxy, phenyl and trifluoromethyl;
In the present invention it is more preferred that Z is selected from:
a single bond, xe2x80x94Oxe2x80x94, and xe2x80x94NR9xe2x80x94,
where R9 is independently selected from hydrogen, C1-6 alkyl, C3-8 cycloalkyl, phenyl, and C1-6 alkyl-phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: C1-3 alkyl, phenyl and C1-3 alkoxy;
In the present invention it is preferred that R1 is selected from:
C1-10 alkyl, cyclohexyl, C0-2 alkyl-phenyl and CH2-cyclohexyl,
which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, C1-3 alkyl, C1-3 alkoxy, trifluoromethoxy and trifluoromethyl.
In the present invention it is more preferred that R1 is selected from:
methyl, iso-butyl, tert-butyl, hexyl, cyclohexyl, CH2-cyclohexyl, and
C0-2 alkyl-phenyl wherein the phenyl is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: chloro, fluoro, methyl, tert-butyl, trifluoromethoxy and trifluoromethyl.
In the present invention it is preferred that R2 is hydrogen.
In the present invention it is preferred that R3 is selected from the group consisting of:
phenyl and thienyl,
which may be unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3 alkyl, and
(e) xe2x80x94Oxe2x80x94C1-3 alkyl.
In the present invention it is more preferred that R3 is selected from the group consisting of:
phenyl and thienyl,
which may be unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) fluoro,
(b) chloro,
(c) trifluoromethyl,
(d) hydroxy, and
(e) C1-3 alkyl.
In the present invention it is even more preferred that R3 is selected from the group consisting of:
phenyl, which may be unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) fluoro, and
(b) chloro; and
unsubstituted thienyl.
In the present invention it is still more preferred that R3 is unsubstituted phenyl, (3-fluoro)phenyl or 3-thienyl.
In the present invention it is preferred that R7 is hydrogen, fluoro, hydroxy or C1-6 alkyl.
In the present invention it is more preferred that R7 is hydrogen or fluoro.
In the present invention it is even more preferred that R7 is hydrogen.
In the present invention it is preferred that R8 is selected from:
C1-6 alkyl, C3-6 cycloalkyl, phenyl, 1-naphthyl, 2-naphthyl, C1-6 alkyl-phenyl, and C1-6 alkyl-C3-6 cycloalkyl,
which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) cyano,
(c) hydroxy,
(d) C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R13 where R13 is independently selected from: halo, cyano, hydroxy, C1-6 alkoxy, xe2x80x94CO2H, phenyl, xe2x80x94CO2(C1-6 alkyl), trifluoromethyl, and xe2x80x94NR9R10, wherein R9 and R10 are independently selected from: hydrogen, C1-6 alkyl, C5-6 cycloalkyl, benzyl or phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl;
(e) xe2x80x94Oxe2x80x94C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R13,
(f) xe2x80x94CF3,
(g) xe2x80x94CHF2,
(h) xe2x80x94CH2F,
(i) xe2x80x94NO2,
(j) phenyl, and
(k) xe2x80x94CO2R9.
In the present invention it is more preferred that R8 is selected from:
C1-6 alkyl, C3-6 cycloalkyl, xe2x80x94CH2-cyclohexyl, phenyl, and xe2x80x94CH2-phenyl, wherein the phenyl is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) halo,
(b) xe2x80x94NO2,
(c) xe2x80x94CF3,
(d) xe2x80x94C1-6 alkyl, and
(e) phenyl.
In the present invention it is even more preferred that R8 is selected from:
methyl, ethyl, n-butyl, tert-butyl, CH2-cyclohexyl, phenyl and
CH2 phenyl, wherein the phenyl is unsubstituted or substituted with a substituent selected from:
(a) fluoro,
(b) chloro
(c) xe2x80x94NO2,
(d) xe2x80x94CF3,
(e) methyl,
(f) phenyl,
(g) 1-naphthyl, and
(n) 2-naphthyl.
In the present invention it is preferred that x is an integer which is 1 and y is an integer which is 1.
It is to be understood that embodiments of the present invention include, but are not limited to, compounds of formula I wherein R1, R2, R3, R7, R8, X, Y, Z, x, and y are defined in accordance with one of the embodiments or aspects thereof as set forth above. Any and all possible combinations of preferred, more preferred, even more preferred, highly preferred, more highly preferred, and most preferred definitions of these variables in formulas I are within the scope of the present invention.
The compounds of the instant invention have at least two asymmetric centers at the ring junction of the substitutents bearing the piperidine and R3. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The relative configurations of the more preferred compounds of this invention are of the trans orientation, i.e. as depicted:
The relative configurations of the even more preferred compounds of this invention with respect to the configuration at the 1-position of the cyclopentane ring is 1,3-trans of the orientation as depicted:
The independent syntheses of these diastereomer their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
As appreciated by those of skill in the art, halo or halogen as used herein are intended to include chloro, fluoro, bromo and iodo. Similarly, C1-8, as in C1-8 alkyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbons in a linear or branched arrangement, such that C1-8 alkyl specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl. Likewise, C0, as in C0 alkyl is defined to identify the presence of a direct covalent bond.
The term xe2x80x9cheterocyclexe2x80x9d (which may alternatively be referred to as xe2x80x9cheterocyclicxe2x80x9d) refers to a 4- to 8-membered monocyclic ring, a 7- to 11-membered bicyclic system, or a 10 to 15-membered tricyclic ring system, any ring of which is saturated or unsaturated (partially or totally), and which consists of carbon atoms and one or more heteroatoms (e.g., from 1 to 4 heteroatoms) selected from N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, the nitrogen heteroatom may optionally be quaternized, and a ring carbon may optionally be oxidized (i.e., is substituted with oxo). The heterocyclic ring may be attached at any heteroatom or carbon atom, provided that attachment results in the creation of a stable structure. A preferred heterocycle is a 4- to 8-membered monocyclic ring or a 7- to 11-membered bicyclic system, as defined and described above.
The term xe2x80x9cheterocyclexe2x80x9d as used herein is intended to include the following groups: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof.
The term xe2x80x9cheterocyclexe2x80x9d as used herein is also intended to include, but is not limited to, the following groups: methylenedioxyphenyl, imidazopyridyl, imidazopyrimidinyl, imidazopyridazinyl, imidazopyrazinyl, imidazotriazinyl, imidazothiopheyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrazolotriazinyl, pyrazolothiophenyl, triazolopyridyl, triazolopyrimidinyl, triazolopyridazinyl, triazolopyrazinyl, triazolothiophenyl, tetrahydroimidazopyridinyl, tetrahydropyrazolopyridinyl, tetrahydrotriazopyridinyl, tetrahydrotriazolopyridazinyl, and tetrahydroindazolyl.
The term xe2x80x9cheterocyclexe2x80x9d as used herein is also intended to include, but is not limited to, the following groups: tetrahydroimidazopyrimidyl, tetrahydroimidazopyrazinyl, tetrahydroimidazopyridazinyl, tetrahydrotriazolopyrimidyl, tetrahydrotriazolopyrazinyl, tetrahydropyrazolopyrimidyl, tetrahydropyrazolopyrazinyl, imidazothiazolyl, and imidazothiadiazolyl.
The term xe2x80x9cheterocyclexe2x80x9d as used herein is also intended to include, but is not limited to, oxopyridinyl (e.g., 2-oxopyridinyl), oxopiperidinyl, and oxopyrazolyl.
The terms xe2x80x9cthiophenylxe2x80x9d and xe2x80x9cthienylxe2x80x9d have the same meaning herein and are used interchangeably. Similarly, the following pairs of terms are used interchangeably: xe2x80x9cindazolylxe2x80x9d and xe2x80x9cbenzopyrazolylxe2x80x9d; xe2x80x9cpyridinylxe2x80x9d and xe2x80x9cpyridylxe2x80x9d.
In the expression xe2x80x9c . . . which is unsubstituted or substituted with . . . xe2x80x9d, xe2x80x9cwhichxe2x80x9d is intended to refer back to all preceding chemical groups in the particular definition in which the expression appears, unless a contrary meaning is expressed or is implied by the context. Furthermore, the term xe2x80x9csubstitutedxe2x80x9d in the expression includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution is chemically allowed in any of the named chemical groups. Thus, for example, the expression xe2x80x9cis independently selected from: hydrogen, C1-6 alkyl, C5-6 cycloalkyl, benzyl or phenyl, which is unsubstituted or substituted with 1-3 substituents . . . xe2x80x9d, encompasses hydrogen, C1-6 alkyl, C5-6 cycloalkyl, benzyl, phenyl, mono- and di- and tri-substituted C1-6 alkyl, mono- and di- and tri-substituted C5-6 cycloalkyl, mono- and di- and tri-substituted benzyl and mono- and di- and tri-substituted phenyl.
Exemplifying the invention is the use of the compounds disclosed in the Examples and herein.
Specific compounds within the present invention include a compound which is selected from the group consisting of:
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
The subject compounds are useful in a method of modulating chemokine receptor activity in a patient in need of such modulation comprising the administration of an effective amount of the compound.
The present invention is directed to the use of the foregoing compounds as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors, including CCR-5 and/or CCR-3.
The utility of the compounds in accordance with the present invention as modulators of chemokine receptor activity may be demonstrated by methodology known in the art, such as the assay for chemokine binding as disclosed by Van Riper, et al., J. Exp. Med., 177, 851-856 (1993) which may be readily adapted for measurement of CCR-5 binding, and the assay for CCR-3 binding as disclosed by Daugherty, et al., J. Exp. Med., 183, 2349-2354 (1996). Cell lines for expressing the receptor of interest include those naturally expressing the receptor, such as EOL-3 or THP-1, or a cell engineered to express a recombinant receptor, such as CHO, RBL-2H3, HEK-293. For example, a CCR3 transfected AML14.3D10 cell line has been placed on restricted deposit with American Type Culture Collection in Rockville, Md. as ATCC No. CRL-12079, on Apr. 5, 1996. The utility of the compounds in accordance with the present invention as inhibitors of the spread of HIV infection in cells may be demonstrated by methodology known in the art, such as the HIV quantitation assay disclosed by Nunberg, et al., J. Virology, 65 (9), 4887-4892 (1991).
In particular, the compounds of the following examples had activity in binding to the CCR-5 or the CCR-3 receptor in the aforementioned assays, generally with an IC50 of less than about 1 xcexcM. Such a result is indicative of the intrinsic activity of the compounds in use as modulators of chemokine receptor activity.
Mammalian chemokine receptors provide a target for interfering with or promoting eosinophil and/or lymphocyte function in a mammal, such as a human. Compounds which inhibit or promote chemokine receptor function, are particularly useful for modulating eosinophil and/or lymphocyte function for therapeutic purposes. Accordingly, the present invention is directed to compounds which are useful in the prevention and/or treatment of a wide variety of inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
For example, an instant compound which inhibits one or more functions of a mammalian chemokine receptor (e.g., a human chemokine receptor) may be administered to inhibit (i.e., reduce or prevent) inflammation. As a result, one or more inflammatory processes, such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, is inhibited. For example, eosinophilic infiltration to inflammatory sites (e.g., in asthma) can be inhibited according to the present method.
Similarly, an instant compound which promotes one or more functions of a mammalian chemokine receptor (e.g., a human chemokine) is administered to stimulate (induce or enhance) an inflammatory response, such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, resulting in the beneficial stimulation of inflammatory processes. For example, eosinophils can be recruited to combat parasitic infections.
In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens).
Diseases and conditions associated with inflammation and infection can be treated using the method of the present invention. In a preferred embodiment, the disease or condition is one in which the actions of eosinophils and/or lymphocytes are to be inhibited or promoted, in order to modulate the inflammatory response.
Diseases or conditions of humans or other species which can be treated with inhibitors of chemokine receptor function, include, but are not limited to: inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as asthma, particularly bronchial asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffler""s syndrome, chronic eosinophilic pneumonia), delayed-type hypersentitivity, interstitial lung diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren""s syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), insect sting allergies; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis, Behcet""s disease; graft rejection (e.g., in transplantation), including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn""s disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory dermatoses such an dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); eosinphilic myositis, eosinophilic fasciutis; cancers with leukocyte infiltration of the skin or organs. Other diseases or conditions in which undesirable inflammatory responses are to be inhibited can be treated, including, but not limited to, reperfusion injury, atherosclerosis, certain hematologic malignancies, cytokine-induced toxicity (e.g., septic shock, endotoxic shock), polymyositis, dermatomyositis.
Diseases or conditions of humans or other species which can be treated with promoters of chemokine receptor function, include, but are not limited to: immunosuppression, such as that in individuals with immunodeficiency syndromes such as AIDS, individuals undergoing radiation therapy, chemotherapy, therapy for autoimmune disease or other drug therapy (e.g., corticosteroid therapy), which causes immunosuppression; immunosuppression due congenital deficiency in receptor function or other causes; and infectious diseases, such as parasitic diseases, including, but not limited to helminth infections, such as nematodes (round worms); (Trichuriasis, Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis); trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tape worms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceral worms, visceral larva migrans (e.g., Toxocara), eosinophilic gastroenteritis (e.g., Anisaki spp., Phocanema ssp.), cutaneous larva migrans (Ancylostona braziliense, Ancylostoma caninum).
The compounds of the present invention are accordingly useful in the prevention and treatment of a wide variety of inflammatory and immunoregulatory disorders and diseases, allergic conditions, atopic conditions, as well as autoimmune pathologies.
In another aspect, the instant invention may be used to evaluate putative specific agonists or antagonists of chemokine receptors, including CCR-5 and/or CCR-3. Accordingly, the present invention is directed to the use of these compounds in the preparation and execution of screening assays for compounds which modulate the activity of chemokine receptors. For example, the compounds of this invention are useful for isolating receptor mutants, which are excellent screening tools for more potent compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other compounds to chemokine receptors, e.g., by competitive inhibition. The compounds of the instant invention are also useful for the evaluation of putative specific modulators of the chemokine receptors, including CCR-5 and/or CCR-3. As appreciated in the art, thorough evaluation of specific agonists and antagonists of the above chemokine receptors has been hampered by the lack of availability of non-peptidyl (metabolically resistant) compounds with high binding affinity for these receptors. Thus the compounds of this invention are commercial products to be sold for these purposes.
The present invention is further directed to a method for the manufacture of a medicament for modulating chemokine receptor activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
The present invention is further directed to the use of these compounds in the prevention or treatment of infection by a retrovirus, in particular, the human immunodeficiency virus (HIV) and the treatment of, and delaying of the onset of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HIV is defined as including, but not 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, organ transplant, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
In a preferred aspect of the present invention, a subject compound may be used in a method of inhibiting the binding of a chemokine to a chemokine receptor, such as CCR-5 or CCR-3, of a target cell, which comprises contacting the target cell with an amount of the compound which is effective at inhibiting the binding of the chemokine to the chemokine receptor.
The subject treated in the methods above is a mammal, preferably a human being, male or female, in whom modulation of chemokine receptor activity is desired. xe2x80x9cModulationxe2x80x9d as used herein is intended to encompass antagonism, agonism, partial antagonism, inverse agonism and/or partial agonism. In a preferred aspect of the present invention, modulation refers to antagonism of chemokine receptor activity. The term xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
The term xe2x80x9ccompositionxe2x80x9d as used herein 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 specified 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 terms xe2x80x9cadministration ofxe2x80x9d and or xe2x80x9cadministering axe2x80x9d compound should be understood to mean providing a compound of the invention to the individual in need of treatment.
Combined therapy to modulate chemokine receptor activity and thereby prevent and treat inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis, and those pathologies noted above is illustrated by the combination of the compounds of this invention and other compounds which are known for such utilities.
For example, in the treatment or prevention of inflammation, the present compounds may be used in conjunction with an antiinflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine-suppressing antiinflammatory agent, for example with a compound such as acetaminophen, asprin, codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like. Similarly, the instant compounds may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antuitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention. Examples of other active ingredients that may be combined with a compound of the present invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) VLA-4 antagonists such as those described in U.S. Pat. No. 5,510,332, WO95/15973, WO96/01644, WO96/06108, WO96/20216, WO96/22966, WO96/31206, WO96/4078 1, WO97/03094, WO97/02289, WO 98/42656, WO98/53814, WO98/53817, WO98/53818, WO98/54207, and WO98/58902; (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus, rapamycin and other FK-506 type immunosuppressants; (d) antihistamines (H1-histamine antagonists) such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and the like; (e) non-steroidal anti-asthmatics such as xcex22-agonists (terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol, and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (zafirlukast, montelukast, pranlukast, iralukast, pobilukast, SKB-106,203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs) such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors of phosphodiesterase type IV (PDE-IV); (i) other antagonists of the chemokine receptors, especially CXCR-4, CCR-1, CCR-2, CCR-3 and CCR-5; (j) cholesterol lowering agents such as HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, and other statins), sequestrants (cholestyramine and colestipol), nicotinic acid, fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), and probucol; (k) anti-diabetic agents such as insulin, sulfonylureas, biguanides (metformin), xcex1-glucosidase inhibitors (acarbose) and glitazones (troglitazone and pioglitazone); (l) preparations of interferon beta (interferon beta-1xcex1, interferon beta-1xcex2); (m) other compounds such as 5-aminosalicylic acid and prodrugs thereof, antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxic cancer chemotherapeutic agents. The weight ratio of the compound of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an NSAID the weight ratio of the compound of the present invention to the NSAID will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
The present invention is further directed to combinations of the present compounds with one or more agents useful in the prevention or treatment of 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 AIDS antivirals, immunomodulators, anti-infectives, or vaccines known to those of ordinary skill in the art.
It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
Preferred combinations are simultaneous or alternating treatments with a compound of the present invention and an inhibitor of HIV protease and/or a non-nucleoside inhibitor of HIV reverse transcriptase. An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. Preferred agents for combination therapy include: Zidovudine, Lamivudine, Stavudine, Efavirenz, Ritonavir, Nelfinavir, Abacavir, Indinavir, 141-W94 (4-amino-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide), N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(2-benzo[b]furanylmethyl)-2(S)-Nxe2x80x2(t-butylcarbox-amido)-piperazinyl))-pentaneamide, and Delavirdine. A preferred inhibitor of HIV protease is indinavir, which is the sulfate salt of N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-Nxe2x80x2-(t-butylcarbo-xamido)-piperazinyl))-pentane-amide ethanolate, and is synthesized according to U.S. Pat. No. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day. Other preferred inhibitors of HIV protease include nelfinavir and ritonavir. Preferred non-nucleoside inhibitors of HIV reverse transcriptase include (xe2x88x92)6-chloro-4(S)-cyclopropylethynyl-4(S)-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, which may be prepared by methods disclosed in EP 0,582,455. The preparation of ddC, ddI and AZT are also described in EPO 0,484,071. These combinations may have unexpected effects on limiting the spread and degree of infection of HIV. Preferred combinations with the compounds of the present invention include the following: (1) Zidovudine and Lamivudine; (2) Stavudine and Lamivudine; (3) Efavirenz; (4) Ritoavir; (5) Nelfinavir; (6) Abacavir; (7) Indinavir; (8) 141-W94; and (9) Delavirdine. Preferred combinations with the compounds of the present invention further include the following (1) indinavir, with efavirenz or (xe2x88x92)6-chloro-4(S)-cyclopropylethynyl-4(S)-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, and, optionally, AZT and/or 3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/or ddI and/or ddC.
Compound A in the foregoing Table 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.
In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans.
The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. 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 specified amounts.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycenrdes. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles.)
The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
In the treatment or prevention of conditions which require chemokine receptor modulation an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. 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. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
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.
Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are either commercially available, are made from known procedures or are prepared as illustrated.
The preparation of cinnamate esters such as 1-3 as intermediates that can be used for the synthesis of compounds within the scope of the instant invention is detailed in Scheme 1. Cinnamate esters of structure 1-3 can be obtained commercially or can be synthesized by reacting a suitable aromatic aldehyde 1-1 with a phosphonoacetate such as 1-2 in the presence of sodium hydride or other bases such as sodium, lithium or potassium hexamethyldisilazide, potassium t-butoxide, and the like. The aldehyde 1-1 can be obtained commercially or can be prepared in a variety of ways from commercial materials (see March J. xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th ed., John Wiley and Sons, New York, pp. 1270-1271 (1992)).
The preparation cyclopentane intermediates having a C-4-aryl substituent within the scope of the instant invention is detailed in Scheme 2 and as described by von A. W. Frahm, Liebigs Ann. Chem., 1969, 728, 21. Treatment of a trans-cinnamic ester such as 2-1 (from Scheme 1) with trimethyl 1,1,2-ethanetricarboxylate (2-2) in the presence of an equivalent of an alkoxide base such as sodium methoxide in refluxing methanol gives the racemic cyclopentane keto-triester 2-3. Hydrolysis of the esters with HCl in acetic acid at reflux with concurrent double decarboxylation affords a mixture of the cis and trans keto-acids 2-4 and 2-5. The predominant initial product is the cis isomer 2-4, however, a better cis:trans ratio of products can be obtained with longer refluxing times. Thus, for example, after 72 h a 3:2 cis:trans ratio is achieved. Esterification of the mixture of acids can be done in a variety of ways, such as with trimethylsilyldiazomethane or acid catalyzed esterification in methanol. The isomers can readily be separated by chromatography and the cis/trans assignment for each is based on literatrure NMR data for 2-6 and 2-7.
The preparation of further cyclopentane intermediates having a C-4 aryl substituent within the scope of the instant invention is detailed in Scheme 3. The trans ketone 3-1 (from Scheme 2) is reduced with sodium borohydride to a near 1:1 mixture of alcohols 3-2 and 3-3, while the cis ketone 3-4 (from Scheme 2) afforded a single cis product after reduction by either sodium borohydride or L-Selectride in THF. The structure 3-5 for the cis reduction product is based on the well established reduction of the cyclopentanones from the least hindered face. The assignment of the trans reduction products was then established by equilibration of 3-5 in methanolic sodium methoxide which only gives enhancement of 3-2 by TLC and NMR.
The preparation cyclopentane intermediates having a C-4 aryl and C-1 ether substituents within the scope of the instant invention is detailed in Scheme 4. Alkylation of either separated alcohol from Scheme 3, such as the lower Rf alcohol 4-1, with a benzyl halide, such as benzyl bromide, can be done in DMF using a strong base such as NaH. Alternatively, alkylation with an xcex1-substituted benzylic alcohol such as 4-3 can be achieved through conversion to its trichloroacetimidate 4-4 and reaction with 4-1 in the presence of a strong acid catalyst such as triflic acid. The latter case results in two racemic diastereomeric products which may be separated by chromatography, but their respective stereochemistries were not assigned.
Use of the higher Rf diastereomer from Scheme 3 results in its respective racemic diastereomers.
Preparation of some 1,3,4-trisubstituted cyclopentanes within the scope of the instant invention is given in Scheme 5. Reduction of ester 5-1 (from Scheme 4), for example, with lithium borohydride, diusobutylaluminum hydride, lithium aluminium hydride, or sodium bis(2-methoxyethoxy)aluminum hydride provides the primary alcohol 5-2. Oxidation to the aldehyde 5-3 can be carried out under numerous conditions, such with DMSO and oxalyl chloride at low temperature, followed by triethylamine (Swern oxidation), with the Dess-Martin periodinane, or with various chromium trioxide-based reagents (see March J. xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th ed., John Wiley and Sons, New York, pp. 1167-1171 (1992)). Reductive amination with a cyclic amine, such as piperidine 5-4 (see Schemes 12 and 13), using for example sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as methylene chloride, 1,2-dichloroethane, THF, acetonitrile or methanol, then provides a 3-((4-substitutedpiperidin-1-yl)methyl)cyclopentane derivative 5-5 which can itself be a chemokine receptor modulator or can be further modified as detailed below in Scheme 14.
An alternative preparation of cyclopentane intermediates having a C-4 aryl substituent within the scope of the instant invention is detailed in Scheme 6A and was used to prepare non-racemic cyclopentane derivatives. Treatment of a trans-cinnamic ester such as 6-1 (see Scheme 1) with 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (6-2) in the presence of a catalytic amount of tetrakis(triphenylphosphine)palladium(0) and 1,2-bis(diphenylphosphino)ethane in THF at reflux afforded the exo-methylene cyclopentane 6-3. Hydrolysis of the ester can be done several ways, such as with aqueous sodium or lithium hydroxide in methanol or THF, to obtain the racemic acid 6-4. Resolution of the enantiomers can be accomplished by fractional crystallization from isopropanol, or other suitable solvents, of the salts with either (R)-(+)- or (S)-(xe2x88x92)-(xcex1-methylbenzyl amine to give the salts 6-5 and 6-6. The non-racemic acids 6-7 and 6-8 are recovered by acidification and extraction. Reesterification to non-racemic 6-9 and 6-10 can be done in a variety of ways, such as with trimethylsilyldiazomethane or acid catalyzed esterification in methanol.
An alternative preparation of non-racemic cyclopentane intermediates having a C-4 aryl sub stituent within the scope of the instant invention is detailed in Scheme 6B. Conversion of the cyclopentane acid 6-4 (from Scheme 6A) to the acid chloride 6-11 under standard conditions, such as with oxalyl chloride in methylene chloride with a catalytic amount of DMF, or to the mixed anhydride 6-12, prepared in situ with trimethylacetyl chloride in ether with TEA as base, followed by reaction with the preformed lithium salt of (S)-(xe2x88x92)-4-benzyl-2-oxazolidinone 6-13, afforded the two non-racemic diastereomeric products 6-14 and 6-15, which are then separable by chromatography. Hydrolysis of each diastereomer under standard conditions, such as with lithium hydroxide and hydrogen peroxide, affords the two non-racemic acids 6-7 and 6-8. Alternatively, in order to obtain an enhanced amount of the desired diastereomer 6-14 before separation, similar conversion of the starting trans-cinnamic acid 6-16 (Scheme 1) to the chiral trans-cinnamate 6-17 followed by the ring formation reaction with 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (6-2) as detailed in Scheme 6A affords a 60:40 product mixture of 6-14:6-15.
An alternative route for the preparation of some 1,3,4-trisubstituted cyclopentanes within the scope of the instant invention is given in Scheme 7. Oxidation of 7-1 (from Scheme 6A, either racemic or non-racemic) with ozone at xe2x88x9273xc2x0 C. in an alcoholic solvent, such as methanol, followed by treatment with dimethyl sulfide affords the ketone 7-2 (same as racemic 2-7 in Scheme 2). Reductive alkylation of methylamine with 7-2, using for example sodium triacetoxyborohydride or sodium cyanoborohydride, followed by acylation with a suffonyl chloride (or other acylation or sulfonylation reagent as detailed in Scheme 10) gives the sulfonamide 7-3 as a mixture of isomers. Reduction of the ester mixture, for example with lithium borohydride at rt to 65xc2x0 C., provides the primary alcohol which is separated by chromatography into the two diastereomers at C-1, 7-4 and 7-5. Oxidation to the aldehyde(s) 7-7 can be carried out under numerous conditions, such as with DMSO and oxalyl chloride at low temperature, followed by triethylamine (Swern oxidation), with the Dess-Martin periodinane, or with various chromium trioxide-based reagents (see March J. xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th ed., John Wiley and Sons, New York, pp. 1167-1171 (1992)). Reductive amination with a cyclic amine, such as piperidine 7-6 (see Schemes 12 and 13), using for example sodium triacetoxyborohydride or sodium cyanoborohydride, then provides a 3-((4-substitutedpiperidin-1-yl)methyl)cyclopentane derivative 7-8 which can itself be a chemokine receptor modulator or can be further modified as detailed below in Scheme 14.
An alternative route for the preparation of some 1,3,4-trisubstituted cyclopentanes within the scope of the instant invention is given in Scheme 8. Reductive alkylation of benzylamine with 8-1 (from Scheme 2 or 6), using for example sodium triacetoxyborohydride or sodium cyanoborohydride, gives 8-2 which can be hydrogenated under standard conditions, such as in methanol in the presence of a palladium catalyst, for example Pd/C or Pearlman""s catalyst, and using either hydrogen under pressure or ammonium formate at reflux, to afford the primary amine 8-3. Acylation with an acyl chloride (or other acylation or sulfonylation reagent as detailed in Scheme 10) gives the amide 8-4 as a mixture of isomers. Reduction of the ester mixture, for example with lithium borohydride at rt to 65xc2x0 C., provides the primary alcohol which may be separated into the two diastereomers at C-1, 8-5 and 8-6. Oxidation to the aldehyde(s) 8-7 can be carried out under numerous conditions, such as with DMSO and oxalyl chloride at low temperature, followed by triethylamine (Swern oxidation), with the Dess-Martin periodinane, or with various chromium trioxide-based reagents (see March J. xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th ed., John Wiley and Sons, New York, pp. 1167-1171 (1992)). Reductive amination with a cyclic amine, such as piperidine 8-8 (see Schemes 12 and 13), using for example sodium triacetoxyborohydride or sodium cyanoborohydride, then provides a 3-((4-substitutedpiperidin-1-yl)methyl)cyclopentane derivative 8-9 which may itself be a chemokine receptor modulator or may be further modified as detailed below in Scheme 14.
An alternative route for the preparation of some 1,3,4-trisubstituted cyclopentanes within the scope of the instant invention is given in Scheme 9. Acylation of the amine 9-1, usually as a mixture of isomers (from Scheme 7 or 8), with a chloroformate gives the carbamate 9-2. Reduction of the ester mixture, for example with lithium borohydride at rt to 65xc2x0 C., provides the primary alcohol which may be separated into the two diastereomers at C-1, 9-3 and 9-4, if 9-1 started as a mixture. Oxidation to the aldehyde 9-5 can be carried out under numerous conditions, such as with DMSO and oxalyl chloride at low temperature, followed by triethylamine (Swern oxidation), with the Dess-Martin periodinane, or with various chromium trioxide-based reagents (see March J. xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th ed., John Wiley and Sons, New York, pp. 1167-1171 (1992)). Reductive amination with a cyclic amine, such as piperidine 9-6 (see Schemes 12 and 13), using for example sodium triacetoxyborohydride or sodium cyanoborohydride, then provides a 3-((4-substitutedpiperidin-1-yl)methyl)cyclopentane derivative 9-7 which may itself be a chemokine receptor modulator or may be further modified as detailed below in Scheme 14.
Another method of preparing compounds within the scope of the instant invention is given in Scheme 10. In the case where Rxe2x80x2 in Scheme 9 is t-butyl (or PMB), such as shown in 10-1, the Boc (or PMB ester) group can be removed with strong acid, such as trifluoroacetic acid at rt or formic acid at rt to 60xc2x0 C., to generate the amine 10-2 which already has the C-3 position fully functionalized. Alternatively, if Rxe2x80x2 in Scheme 9 is PMB or benzyl, amine 10-2 can be generated by standard hydrogenation, the choice of carbamate depends on the compatability with R. The amine of 10-2 can then be converted to a variety of nitrogen based derivatives at the C-1 position. For example, acylation with an alkyl or aryl acid chloride, or a carboxylic acid plus an activating agent, such as EDC, DCC, DIC or BOP-Cl, affords amide 10-3. Use of an alkyl or aryl sulfonyl chloride gives sulfonamides 10-4, use of an alkyl or aryl chloroformate gives carbamates 10-5, use of an alkyl or aryl carbamoyl chloride or isocyanate gives ureas 10-6 and 10-7, and use of an alkyl or aryl isothiocyanate gives thioureas 10-8. These reaction can be done in a variety of suitable solvents, such as methylene chloride, dichloroethane, THF or methanol. For each of these reactions, an amine base is employed, such as TEA, DIPEA, n-methyl morpholine, pyridine or 2,6-lutidine. Alternatively, reductive alkylation with an aldehyde or ketone with a suitable reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride, in a suitable solvent, such as methylene chloride or dichloroethane, can afford the di-basic amine derivative 10-9.
Another method of preparing compounds within the scope of the instant invention is given in Scheme 11. Reduction of either ester 11-1 with lithium aluminum hydride or lithium borohydride or acid 11-2 with lithium aluminum hydride affords the exo-methylene alcohol 11-3. Oxidation 11-3 to the aldehyde 11-4 can be carried out under numerous conditions, such as with DMSO and oxalyl chloride at low temperature, followed by triethylamine (Swern oxidation), with the Dess-Martin periodinane, or with various chromium trioxide-based reagents (see March J. xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th ed., John Wiley and Sons, New York, pp. 1167-1171 (1992)). Reductive alkylation of a cyclic amine, such as piperidine 11-5 (see Schemes 12 and 13) with 11-4, using for example sodium triacetoxyborohydride or sodium cyanoborohydride, then provides a 3-((4-substitutedpiperidin-1-yl)methyl)cyclopentane derivative 11-6. Oxidation of the exo-methylene of 11-6 to a ketone 11-7 can be done on the hydrochloride salt of 11-6 in methanol with ozone at xe2x88x9273xc2x0 C. followed by dimethyl sulfide work-up. Reductive alkylation of a primary or secondary amine with 11-7 using for example sodium triacetoxyborohydride or sodium cyanoborohydride affords the amine 11-8 which itself can be a chemokine receptor modulator or can be further modified as already detailed in Schemes 7-10. Thus, if R2 of 11-8 is H, further functionalization of 11-8 as detailed in Scheme 10 can afford 11-10 as other examples of chemokine receptor modulators. Alternatively, if R2 is benzyl or some other amine protecting group, and the piperidine substituent R is stable to hydrogenation or other means for removing the R2 group to give 11-9, then further functionalization to 11-10 is also possible.
Synthetic routes for the preparation of piperidines bearing a 4-substituent containing an amide, carbamate, sulfonamide or urea functional group are given in Scheme 12. Reductive amination of commercially available 12-1 or 12-2 with primary amine 12-3 in the presence of sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent (for example, methylene chloride, 1,2-dichloroethane, THF, acetonitrile, or methanol) provides amines 12-4 or 12-5. Acylation is then carried out with an acyl chloride (or a carboxylic acid plus an activating agent, such as EDC, DCC, or BOP-Cl) to provide 12-6 or 12-7 as an amide. Alternatively, acylation with a chloroformate provides 12-6 or 12-7 as a carbamate. Treatment of 12-4 or 12-5 with an isocyanate affords 12-6 or 12-7 as a urea. Treatment of 12-4 or 12-5 with a sulfonyl chloride affords 12-6 or 12-7 as a sulfonamide. For each of these reactions, an amine base is employed, such as triethylamine, DEEA, pyridine, or 2,6-lutidine. In the case of the benzyl-protected derivative 12-7, hydrogenolysis under standard conditions (for example, hydrogen in the presence of palladium on carbon in methanol or ethanol) provides the desired intermediate 12-8. For the N-Boc compound 12-6, exposure to suitable anhydrous acidic conditions (for example trifluoroacetic acid and anisole in methylene chloride at temperatures from 0-25 degrees C.) affords the salt of 12-8. This compound is then utilized as the cyclic secondary amine component as shown above in Schemes 5, 7, 8, 9, and 11. Alternatively, if no functionality are present in the alkyl cyclopentane framework that would be adversely effected by the above mentioned chemistry, then 4-piperidone may be attached directly to the alkyl cyclopentane framework described above, and the chemistry described in this paragraph can be carried out equating the alkyl cyclopentane segment to the group xe2x80x98Pxe2x80x99 given in Scheme 12, structures 1 through 7 (also see Scheme 14).
Alternate synthetic routes for the preparation of piperidines bearing a 4-substituent containing an amide, carbamate or urea functional group are given in Scheme 13. Protection of 4-bromopiperidine can be carried out with several protecting groups for nitrogen. For example, using standard conditions, protection with a Boc group gives 13-2, whereas reductive amination with benzaldehyde yields the N-benzyl derivative 13-3. Displacement of the bromide with sodium azide in warm to hot DMF provides the 4-azidopiperidine derivative, and reduction of the azide with hydrogen in the presence of a palladium catalyst (for the Boc protected intermediate) or with triphenylphosphine followed by hydrolysis (for N-benzyl protected intermediate) provides the aminopiperidine 13-4 or 13-5. Acylation is then carried out with an acyl chloride (or a carboxylic acid plus an activating agent, such as EDC, DCC, or BOP-Cl) to provide 13-6 or 13-7 as an amide. Alternatively, acylation with a chloroformate provides 13-6 or 13-7 as a carbamate. Treatment of 13-4 or 13-5 with an isocyanate affords 13-6 or 13-7 as a urea. Treatment of 13-4 or 13-5 with a sulfonyl chloride affords 13-6 or 13-7 as a sulfonamide. For each of these reactions, an amine base is employed, such as triethylamine, DIEA, pyridine, or 2,6-lutidine. When Q=C(Rc)H or O, compounds 13-6 and 13-7 may optionally be alkylated by treatment with a base such as sodium hydride, potassium hydride, LiHMDS, KHMDS, or NAHMDS followed by treatment with an alkyl iodide, allyl halide, or propargyl halide. Solvents such as DMF, DMSO, N-methylpyrrolidine or THF are suitable. These procedures provide carbamate, sulfonamide or amide 13-8 and 13-9. Removal of the protecting groups is then carried out as shown in Scheme 12 above, and the resulting 1-unsubstituted piperidines are then utilized as noted in the descriptions for Schemes 5, 7, 8, 9, and 11.
Another method of preparing compounds within the scope of the instant invention is given in Scheme 14. When the R substituent on the cyclic amine portion in Scheme 5, 7, 8, 9 or 11 is a N-(benzyloxycarbonyl)-N-(alkyl)amino as in 14-1, removal of the benzyloxycarbonyl group by hydrogenation with Pd/C or Pearlman""s catalyst in the presence of hydrogen, ammonium formate or other hydrogen transfer reagent can be done to afford the amine 14-2, as long as the functionality at C-1 of the cyclopentyl ring is stable to the hydrogenation conditions. Alternatively, when the R substituent on the cyclic amine portion is a N-(t-butoxycarbonyl)-N-(alkyl)amino as in 14-3, deprotection of 14-3 with strong acid such as TFA or formic acid at rt to 60xc2x0 C. will again give 14-2, as long as the functionality at C-1 of the cyclopentyl ring is stable to the acidic conditions. The exposed amine can then be re-functionalized with a variety of alkyl or aryl acyl or sulfonyl groups (same as in Scheme 10) to afford other examples of chemokine receptor modulators, such as amides 14-4, carbamates 14-5, sulfonamides 14-6 and ureas 14-7.
Another method of preparing compounds within the scope of the instant invention is given in Scheme 15 in which most of the chemistry is done on a resin. This linker methodology employed is that as described by G. W. Kenner, J. Chem. Soc., Chem. Comm., 1971, 636 or any other suitable sulfonamide linker known in the art. Thus, the keto-acid 15-3, prepared either by standard hydrolysis of the ester 15-1 (from Scheme 2 or 7) or oxidation of the exo-methylene of 15-2 (from Scheme 6A or 6B) with ozone in methanol at xe2x88x9270xc2x0 C. followed by treatment with dimethyl sulfide, is first activated as its anhydride 15-4 by treatment with a dehydrating agent, such as dicyclohexylcarbodiimide or diisopropylcarbodiimide, in a suitable solvent, such as THF or methylene chloride or a mixture of these, with a catalytic amount of DMAP. Reaction of 15-4 with the Kenner sulfonamide linker 15-5 (4-sulfamylbenzoyl AM resin, Novabiochem, cat.# 01-64-0121), affords the resin-bound cyclopentanone 15-6. Reductive amination under standard conditions, such as with sodium triacetoxyborohydride in THF or 1,2-dichloroethane, of various amines with 15-6 affords the resin-bound amino derivative 15-7. Acylation or sulfonylation can be done under standard conditions, such as with alkyl or aryl acid chlorides, sulfonyl chlorides, isocyanates, isothiocyanates, chloroformates, carbamoyl chlorides or other standard acylating agent, usually in the presence of an amine base, such as triethylamine, diisopropylethylamine, N-methylmorpholine, or pyridine, to afford the resin-bound amine derivative 15-8. Activation of the resin sulfonamide linker with trimethylsilyldiazomethane and displacement with an amine, such as the piperidine 15-9 (see Schemes 12 and 13) in which R must be stable to borane-dimethyl sulfide reduction, gives the corresponding amide 15-10. Subsequent reduction of the amide 15-10 with borane-dimethyl sulfide can then afford a variety of examples of chemokine receptor modulators. If the C-1 amine derivative in 15-10 (xe2x80x94Nxe2x80x94Xxe2x80x94) is also reducible under these conditions, then a corresponding diamine 15-11 (X=CH2) will be obtained which can also be a chemokine receptor modulator. Alternatively, the diamine 15-11 (X=CH2) could have been obtained using a second reductive amination step in place of the acylation reaction. Alternatively, for the preparation of amine derivatives which are not stable to the diborane-methyl sulfide conditions, such as for the amide moiety (15-10, X=xe2x80x94COxe2x80x94), the acylation step can be done after the cleavage/reduction sequence as detailed in Scheme 10. When either R or Rxe2x80x2 are suitable for further elaboration as detailed in Schemes 10 or 14, additional derivatives can also be prepared.
Another method of preparing compounds within the scope of the instant invention is given in Scheme 16. Reduction of the ester 16-1 (R=Me, from Scheme 6A) with either LAH or LiBH4 in THF affords the alcohol 16-2. Alternatively, reduction of the acid 16-1 (R=H, from Scheme 6A or 6B) with LAH in THF can also afford 16-2. Silylation of the alcohol with TBDMS-Cl in THF or methylene choride in the presence of a base, such as TEA or DIPEA, followed by oxidation of the exo-methylene with ozone in methanol at reduced temperature, such as at xe2x88x9270xc2x0 C., using a reductive work-up with dimethylsulfide gives the protected alcohol-ketone 16-3. Alternatively, the silylation and oxidation steps can be reversed. Reaction of the ketone of 16-3 with benzyltriphenylphophonium bromide in the presence of a base such as potassium t-butoxide gives a mixture of the benzylidene isomers 16-4 and 16-5 which may be separable by chromatographic methods at this step or at a later stage. Hydrogenation under standard conditions with Pd/C or Pearlman""s catalyst in methanol affords the benzyl derivatives 16-6 and/or 16-7. The silyl ether can then be removed under standard conditions with acidic methanol or TBAF in THF to afford the alcohols 16-8 and/or 16-9 which also may be separable by chromatographic methods. Alternatively, the hydrogenation and silyl removal may be interchanged. The alcohols 16-8 and/or 16-9 can be converted to the final product(s) 6-10 and 6-11 as shown in Scheme 5.
Another method of preparing compounds within the scope of the instant invention is given in Scheme 17. Hydroborantion of 17-1 (see Scheme 16) using borane-THF or borane-Me2S complex in THF followed by a standard oxidative work-up with sodium hydroxide and hydrogen peroxide or trimethylamine-N-oxide affords the C-1 hydroxymethyl compound 17-2 as a mixture of C-1 isomers. Oxidation to the aldehyde 17-3 can be done under Swern conditions or with a variety of other reagents (see above). Addition of an aryl lithium (commercially available or prepared from the aryl iodide or bromide and t-butyl lithium in THF at reduced temperature, such as at xe2x88x9278xc2x0 C.) or an aryl magnesium iodide or bromide (Grignard reagent) (commercially available or prepared from the aryl iodide or bromide and magnesium in THF or ether) to the aldehyde 17-3 gives a mixture of the four possible C-1 and C-1xe2x80x2 isomers 17-4. Reoxidation again using Swern conditions followed by desilylation gives the aroyl derivatives which may be separable by chromatographic methods to afford the individual C-1 isomers 17-5 and 17-6. Alternatively, 17-4 can be catalytically reduced under standard conditions with Pd/C or Pearlman""s catalyst in methanol to afford the arylmethyl derivatives 17-7 and 17-8 after desilylation. These may be separable by chromatographic methods and gives an alternative preparation of 16-6 and 16-7 as shown in Scheme 16. Alternatively, the hydrogenation and silyl removal may be interchanged. The alcohols 17-5 and/or 17-6 and 17-7 and/or 17-8 can be converted to the final product(s) 17-9 and 17-10 as shown in Scheme 5.
Another method of preparing compounds within the scope of the instant invention is given in Scheme 18. Reaction of the silyl-ketone 18-1 (see Scheme 16) with NaBU4 in methanol under standard conditions gives 18-2 as a mixture of isomers. Reaction of 18-2 with a hydroxyaryl in the presence of triphenylphosphine and DEAD leads to the formation of the ethers 18-4 and 18-5 which may be separable by chromatographic methods either before or after the desilylation to 18-5 and/or 18-6. The alcohols 18-5 and/or 18-6 can be converted to the final product(s) 18-7 and 18-8 as shown in Scheme 5.

Cyclopentyl modulators of chemokine receptor activity

Abstract: (wherein R1, R2, R3, R7, R8, X, Y, Z, x and y are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-5 and/or CCR-3.


A redundancy architecture for repairing a DRAM includes fuse banks for storing the row addresses of defective rows in sub-arrays of the DRAM. Row decoders activate a redundant row in one of the sub-arrays in response to receiving a row address matching one of the stored defective row addresses and, at the same time, disable a redundant row in the other of the sub-arrays that is arranged in an order complementary to that of the activated redundant row. By activating a redundant row in one sub-array and disabling the corresponding redundant row in an adjacent sub-array, the architecture allows for repairs to be conducted in the one sub-array while a good row in the adjacent sub-array is allowed to continue in operation. Also, since the redundant row used for repairs in the one sub-array is typically nearest the center of the sub-array, the disabled redundant row in the adjacent sub-array is nearest the edge of that sub-array, because it is arranged in an order complementary to that of the redundant row used for repairs. As a result, the disabled redundant row acts as an edge buffer between the primary and redundant rows of the adjacent sub-array and peripheral circuitry.

1. Technical Field
This invention relates to memory cell redundancy in semiconductor memories.
2. State of the Art
Semiconductor memories generally include a multitude of memory cells arranged in rows and columns. Each memory cell is capable of storing digital information in the form of a "1" or a "0" bit. To write (i.e., store) a bit into a memory cell, a binary memory address having portions identifying the cell's row (the "row address") and column (the "column address") is provided to addressing circuitry in the semiconductor memory to activate the cell, and the bit is then supplied to the cell. Similarly, to read (i.e., retrieve) a bit from a memory cell, the cell is again activated using the cell's memory address, and the bit is then output from the cell.
Semiconductor memories are typically tested after they are fabricated to determine if they contain any failing memory cells (i.e., cells to which bits cannot be dependably written or from which bits cannot be dependably read). Generally, when a semiconductor memory is found to contain failing memory cells, an attempt is made to repair the memory by replacing the failing memory cells with redundant memory cells provided in redundant rows or columns in the memory.
Conventionally, when a redundant row is used to repair a semiconductor memory containing a failing memory cell, the failing cell's row address is permanently stored (typically in pre-decoded form) on a chip on which the semiconductor memory is fabricated by programming a non-volatile element (e.g., a group of fuses, anti-fuses, or FLASH memory cells) on the chip. Then, during normal operation of the semiconductor memory, if the memory's addressing circuitry receives a memory address including a row address that corresponds to the row address stored on the chip, redundant circuitry in the memory causes a redundant memory cell in the redundant row to be accessed instead of the memory cell identified by the received memory address. Since every memory cell in the failing cell's row has the same row address, every cell in the failing cell's row, both operative and failing, is replaced by a redundant memory cell in the redundant row.
Similarly, when a redundant column is used to repair the semiconductor memory, the failing cell's column address is permanently stored (typically in pre-decoded form) on the chip by programming a non-volatile element on the chip. Then, during normal operation of the semiconductor memory, if the memory's addressing circuitry receives a memory address including a column address that corresponds to the column address stored on the chip, redundant circuitry in the memory causes a redundant memory cell in the redundant column to be accessed instead of the memory cell identified by the received memory address. Since every memory cell in the failing cell's column has the same column address, every cell in the failing cell's column, both operative and failing, is replaced by a redundant memory cell in the redundant column.
The process described above for repairing a semiconductor memory using redundant rows and columns is well known in the art, and is described in various forms in U.S. Pat. Nos. 4,459,685, 4,598,388, 4,601,019, 5,031,151, 5,257,229, 5,268,866, 5,270,976, 5,287,310, 5,355,340, 5,396,124, 5,422,850, 5,471,426, 5,502,674, 5,511,028, 5,544,106, 5,572,470, 5,572,471, and 5,583,463.
From the discussion of semiconductor memories thus far, it may appear that such memories comprise one large array of memory cells. This is true as far as other electronic devices are concerned, because such devices typically interact with a semiconductor memory as if it were a single array of memory cells arranged in as many rows and columns (referred to as "global" rows and columns) as are uniquely addressable by the memory's row and column addresses.
However, internally, a modern semiconductor memory most often comprises multiple sub-arrays of memory cells, each containing "local" rows and columns that are portions of the memory's global rows and columns. Thus, for example, a 1 MB semiconductor memory addressable with 1,024 unique row and column addresses typically comprises four 256 KB sub-arrays, with each sub-array containing 512 local rows and columns, and each local row or column being one-half of a global row or column. As a result, each row address provided to the semiconductor memory uniquely addresses a global row comprised of two local rows in separate sub-arrays, and each column address provided to the memory then uniquely addresses a memory cell in one of the sub-arrays.
In such a semiconductor memory, because row addresses only uniquely address global rows, and do not uniquely address local rows, all local rows that make up a particular global row are activated when that global row is addressed. Similarly, all of the local rows that make up a global row are disabled and replaced with local redundant rows in their respective sub-arrays when a defective memory cell is found anywhere in the global row. Thus, for example, in the case of the 1 MB semiconductor memory discussed above, a defective memory cell in a local row of one sub-array is repaired by replacing the local row with a local redundant row in the sub-array. At the same time, however, a local row in an adjacent sub-array is also replaced with a local redundant row in that sub-array, despite the fact that the local row in the adjacent sub-array has no defects. This occurs because the addressing scheme of the semiconductor memory does not allow local rows to be uniquely addressed.
The conventional redundancy architecture described above is illustrated in FIG. 1. In normal operation, row decoders <0> and <1> activate selected wordline signals, and thereby activate selected rows within adjacent sub-arrays <0> and <1>, in accordance with row addresses they receive. Thus, when a row address selects a particular global row comprised of local rows in the sub-arrays <0> and <1>, row decoders <0> and <1> fire the wordline signals necessary to activate those local rows. Data is then written to, or read from, a memory cell in one of the sub-arrays <0> and <1> selected in accordance with a column address.
If a defective memory cell 10 is found in a local row LR.sub.-- 32 of the sub-array <0>, for example, then the row address of the global row with which the local row LR.sub.-- 32 is associated is stored in fuse banks 12. During subsequent memory operations, when a received row address matches the row address stored in the fuse banks 12, match signals output by the fuse banks 12 direct the row decoders <0> and <1> to not activate the local rows LR.sub.-- 32 in sub-arrays <0> and <1> and, instead, to activate redundant rows RR.sub.-- 0 in sub-arrays <0> and <1>. As a result, the defective memory cell 10 is repaired.
It can be seen from this description that a few defective memory cells in either of the sub-arrays <0> and <1> will very quickly use up the redundant rows RR.sub.-- 0, RR.sub.-- 1, RR.sub.-- 2, and RR.sub.-- 3 available in the sub-arrays <0> and <1>. Since redundant rows are typically formed at the edge of sub-arrays, a few repairs thus very quickly make such sub-arrays dependent on rows positioned right at their edges for normal operations. Since "edge" rows are more likely to have various fabrication errors and are more likely to be affected by the operations of peripheral circuitry, it is undesirable to have sub-arrays routinely dependent for normal operations on edge rows. This is especially true when the local row replaced (e.g., the local row LR.sub.-- 32 in the sub-array <1>) has no defective memory cells, and yet is still replaced with a redundant row (e.g., the redundant row RR.sub.-- 0 of the sub-array <1>) near the edge.
Therefore, there is a need in the art for a device and method for repairing a semiconductor memory that does not require the replacement of a good local row in a sub-array with a redundant row in that sub-array simply because a bad local row in an adjacent sub-array needs to be replaced with a redundant row in the adjacent sub-array. Also, there is a need for a device and method of conducting repairs that limits the use of redundant rows at the extreme edges of sub-arrays so that repairs can be more reliable.

Device and method for repairing a semiconductor memory