Heteroaryl-hexanoic acid amide derivatives, their...

Details Heteroaryl-hexanoic acid amide derivatives, their... Heteroaryl-hexanoic acid amide derivatives, their...

2000-05-18

2002-06-11

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S311000, C514S312000, C544S355000, C546S152000

Reexamination Certificate

active

06403587

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to novel hexanoic acid derivatives, methods of use and pharmaceutical compositions containing them.
The compounds of the invention are potent and selective inhibitors of MIP-1&agr; binding to its receptor CCR1 found on inflammatory and immunomodulatory cells (preferably leukocytes and lymphocytes). The CCR1 receptor is also sometimes referred to as the CC-CKR1 receptor. These compounds also inhibit MIP-1&agr; (and the related chemokine shown to interact with CCR1 (e.g., RANTES and MCP-3)) induced chemotaxis of THP-1 cells and human leukocytes and are potentially useful for the treatment or prevention of autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult Respiratory Distress Syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), transplantation tissue rejection (chronic and acute), organ rejection (chronic and acute), atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis).
MIP-1&agr; and RANTES are soluble chemotactic peptides (chemokines) which are produced by inflammatory cells, in particular CD8+ lymphocytes, polymorphonuclear leukocytes (PMNs) and macrophages,
J.Biol. Chem.,
270 (30) 29671-29675 (1995). These chemokines act by inducing the migration and activation of key inflammatory and immunomodulatory cells. Elevated levels of chemokines have been found in the synovial fluid of rheumatoid arthritis patients, chronic and rejecting tissue transplant patients and in the nasal secretions of allergic rhinitis patients following allergen exposure (Teran , et al.,
J. Immunol.,
1806-1812 (1996), and Kuna et al.,
J. Allergy Clin. Immunol.
321 (1994)). Antibodies which interfere with the chemokine/receptor interaction by neutralizing MIP1&agr; or gene disruption have provided direct evidence for the role of MIP-1&agr; and RANTES in disease by limiting the recruitment of monocytes and CD8+ lymphocytes (Smith et al.,
J. Immunol,
153, 4704 (1994) and Cook et al.,
Science,
269, 1583 (1995)). Together this data demonstrates that CCR1 antagonists would be an effective at treatment of several immune based diseases. The compounds described within are potent and selective antagonists of CCR1. No other small molecule antagonists of the MIP-1&agr;/RANTES interaction with CCR1 are currently known.
U.S. Pat. No. 4,923,864, issued May 8, 1990, refers to certain heterocyclic hexanamides that are useful for treating hypertension.
PCT publication WO 89/01488, published Feb. 23, 1989, refers to renin inhibiting peptides which possess nonpeptide linkages.
PCT publication WO 93/ 025057, published Feb. 4, 1993, refers to dipeptide analogs which are claimed to inhibit retroviral proteases.
PCT publication WO 93/17003, published Sep. 2, 1993, refers to other dipeptide analogs which are claimed to inhibit retroviral proteases.
PCT publication WO 92/17490, published Oct. 15, 1992, refers to peptides containing at least one O-phosphate monoester or diester. The compounds are claimed to possess activity for inhibiting retroviruses.
European Patent Publication 708,085, published Apr. 24, 1996, refers to antiviral ethers of aspartate protease inhibitors.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
wherein
R
1
is (C
2
-C
9
)heteroaryl optionally substituted with one or more substituents (preferably one to three substituents) independently selected from the group consisting of hydrogen, halo, CN, (C
1
-C
6
)alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, HO—(C═O)—, (C
1
-C
6
)alkyl-O—(C═O)—, HO—(C═O)—(C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl-O—(C═O)—(C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl-(C═O)—O—, (C
1
-C
6
)alkyl-(C═O)—O—(C
1
-C
6
)alkyl, H(O═C)—, H(O═C)—(C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl(O═C)—, (C
1
-C
6
)alkyl(O═C)—(C
1
-C
6
)alkyl, NO
2
, amino, (C
1
-C
6
)alkylamino, [(C
1
-C
6
]
2
amino, amino(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylamino(C
1
-C
6
)alkyl, [(C
1
-C
6
)alkyl]
2
amino(C
1
-C
6
)alkyl, H
2
N—(C═O)—, (C
1
-C
6
)alkyl-NH—(C═O)—, [(C
1
-C
6
)alkyl]
2
N—(C═O)—, H
2
N(C═O)—(C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl-HN(C═O)—(C
1
-C
6
)alkyl, [(C
1
-C
6
)alkyl]
2
N—(C═O)—(C
1
-C
6
)alkyl, H(O═C)—NH—, (C
1
-C
6
)alkyl(C═O)—NH, (C
1
-C
6
)alkyl(C═O)—[NH](C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl(C═O)—[N(C
1
-C
6
)alkyl](C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl-S—, (C
1
-C
6
)alkyl-(S═O)—, (C
1
-C
6
)alkyl-SO
2
—, (C
1
-C
6
)alkyl-SO
2
—NH—, H
2
N—SO
2
—, H
2
N—SO
2
—(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylHN—SO
2
—(C
1
-C
6
)alkyl, [(C
1
-C
6
)alkyl]
2
N—SO
2
—(C
1
-C
6
)alkyl, CF
3
SO
3
—, C
1
-C
6
)alkyl-SO
3
—, phenyl, (C
3
-C
10
)cycloalkyl, (C
2
-C
9
)heterocycloalkyl, and (C
2
-C
9
)heteroaryl;
R
2
is phenyl-(CH
2
)
m
—, naphthyl-(CH
2
)
m
—, (C
3
-C
10
)cycloalkyl-(CH
2
)
m
—, (C
1
-C
6
)alkyl or (C
2
-C
9
)heteroaryl-(CH
2
)
m
—, wherein m is an interger from zero to four, wherein each of said phenyl, naphthyl, (C
3
-C
10
)cycloalkyl or (C
2
-C
9
)heteroaryl moieties of said phenyl-(CH
2
)
m
—, naphthyl-(CH
2
)
m
—, (C
3
-C
10
)cycloalkyl-(CH
2
)
m
— or (C
2
-C
9
)heteroaryl-(CH
2
)
m
— groups may optionally be substituted with one or more substituents (preferably one to three substituents) independently selected from hydrogen, halo, CN, (C
1
-C
6
)alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, HO—(C═O)—, (C
1
-C
6
)alkyl-O—(C═O)—, HO—(C═O)—(C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl-O—(C═O)—(C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl-(C═O)—O—, (C
1
-C
6
)alkyl-(C═O)—O—(C
1
-C
6
)alkyl, H(O═C)—, H(O═C)—(C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl(O═C)—, (C
1
-C
6
)alkyl(O═C)—(C
1
-C
6
)alkyl, NO
2
, amino, (C
1
-C
6
)alkylamino, [(C
1
-C
6
)alkyl]
2
amino, amino(C
1
-C
6
)alkylamino(C
1
-C
6
)alkyl, [(C
1
-C
6
)alkyl]
2
amino(C
1
-C
6
)alkyl, H
2
N—(C═O)—(C
1
-C
6
)alkyl-NH—(C═O)—, [(C
1
-C
6
)alkyl]
2
N—(C═O)—, H
2
N(C═O)—(C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl-HN(C═O)—(C
1
-C
6
)alkyl, [(C
1
-C
6
)alkyl]
2
N—(C═O)—(C
1
-C
6
)alkyl, H(O═C)—NH—, (C
1
-C
6
)alkyl(C═O)—NH, (C
1
-C
6
)alkyl(C═O)—[NH(C
1
-C
6
)alkyl, (C
1
-C
6
alkyl(C═O)—[N(C
1
-C
6
)alkyl](C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl-S—, (C
1
-C
6
)alkyl-(S═O)—, (C
1
-C
6
)alkyl-SO
2
—, (C
1
C
6
)alkyl-SO
2
—NH—, H
2
N—SO
2
—, H
2
N—SO
2
—(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylHN—SO
2
—(C
1
-C
6
)alkyl, [(C
1
-C
6
)alkyl]
2
N—SO
2
—(C
1
-C
6
)alkyl, CF
3
SO
3
—, (C
1
-C
6
)alkyl-SO
3
—, phenyl, phenoxy, benzyloxy, (C
3
—C
10
)cycloalkyl, (C
2
-C
9
)heterocycloalkyl, and (C
2
-C
9
)heteroaryl;
R
3
is hydrogen, (C
1
-C
10
)alkyl, (C
3
-C
10
)cycloalkyl-(CH
2
)
n
—, (C
2
-C
9
)heterocycloalkyl-(CH
2
)
n
—, (C
2
-C
9
)heteroaryl-(CH
2
)
n
— or aryl-(CH
2
)
n
—; wherein n is an interger from zero to six;
wherein said R
3
(C
1
-C
10
)alkyl group may optionally be substituted with one or more substituents, (preferably from one to three substituents) independ

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