Immunotherapeutic agents

Details Immunotherapeutic agents Immunotherapeutic agents

2001-07-20

2003-02-11

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S301000, C514S303000, C514S373000, C514S397000, C514S421000, C546S113000, C546S114000, C546S118000, C548S210000, C548S211000, C548S302700, C548S404000, C548S453000

Reexamination Certificate

active

06518281

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to a method of reducing the level of cytokines and their precursors in mammals and to compounds and compositions useful therein.
In particular, the invention pertains to a class of compounds which inhibit the action of phosphodiesterases, particularly PDE III and PDE IV, and the formation of TNF&agr; and NF
&kgr;
B. In a first embodiment, the compounds of the present invention can be diagrammatically represented by the formula:
 in which:
R
5
is:
(i) the divalent residue of pyridine, pyrrolidine, imidizole, or thiophene, wherein the two bonds of the divalent residue are on vicinal ring carbon atoms;
(ii) a divalent cycloalkyl of 4 to 10 carbon atoms, unsubstituted or substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo;
(iii) di-substituted vinylene, substituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo; or
(iv) ethylene, unsubstituted or substituted with 1 to 2 substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino, substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo;
R
6
is —CO—, —CH
2
—, —CH
2
CO—, or —SO
2
—;
R
7
is
(i) cyclic or bicyclic alkyl of 4 to 12 carbon atoms;
(ii) pyridyl;
(iii) phenyl substituted with one or more substituents each selected independently of the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, straight or branched alkyl of 1 to 10 carbon atoms, straight or branched alkoxy of 1 to 10 carbon atoms, or halo;
(iv) benzyl substituted with one to three substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo;
(v) naphthyl; or
(vi) benzyloxy;
Y is —COX, —C≡N, —OR
8
, alkyl of 1 to 5 carbon atoms, or aryl;
X is —NH
2
, —OH, —NHR,
13
R
9
, —OR
9
, or alkyl of 1 to 5 carbon atoms;
R
8
is hydrogen or lower alkyl;
R
9
is alkyl or benzyl; and,
n has a value of 0, 1, 2, or 3.
Within this group, Y is preferably —C≡N or —CO(CH
2
)
m
CH
3
in which m has a value of 0, 1, 2, or 3; and
In a second embodiment, the compounds of the present invention can be diagrammatically represented by the formula:
 in which:
one of R
1
and R
2
is R
3
—X— and the other is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy, halo, or R
3
—X—;
R
3
is monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, or benzocyclic alkyl of up to 10 carbon atoms;
X is —CH
2
— or —O—;
R
5
is:
(i) the vicinally divalent residue of pyridine, pyrrolidine, imidizole, or thiophene, wherein the two bonds of the divalent residue are on vicinal ring carbon atoms;
(ii) a vicinally divalent cycloalkyl of 4-10 carbon atoms, unsubstituted or substituted with 1 to 3 substituents each selected independently from the group consisting of nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl;
(iii) di-substituted vinylene, substituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo; or
(iv) ethylene, unsubstituted or substituted with 1 to 2 substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo;
R
6
is —CO—, —CH
2
—, or —CH
2
CO—;
Y is —COX, —C≡N, —OR
8
, alkyl of 1 to 5 carbon atoms, or aryl;
X is —NH
2
, —OH, —NHR, —R
9
, —OR
9
, or alkyl of 1 to 5 carbon atoms;
R
8
is hydrogen or lower alkyl;
R
9
is alkyl or benzyl; and,
n has a value of 0, 1, 2, or 3.
The term alkyl as used herein denotes a univalent saturated branched or straight hydrocarbon chain. Unless otherwise stated, such chains can contain from 1 to 18 carbon atoms. Representative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, and the like. When qualified by “lower”, the alkyl group will contain from 1 to 6 carbon atoms. The same carbon content applies to the parent term “alkane” and to derivative terms such as “alkoxy”.
The term cycloalkyl as used herein denotes a univalent saturated cyclic hydrocarbon chain. Unless otherwise stated, such chains can contain up to 18 carbon atoms. Monocyclicalkyl refers to groups having a single ring group. Polycycloalkyl denotes hydrocarbon systems containing two or more ring systems with two or more ring carbon atoms in common. Benzocycloalkyl signifies a monocyclicalkyl group fused to a benzo group.
Representative of monocycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentadecyl, cyclohexadecyl, cycloheptadecyl, and cyclooctadecyl. Representative of polycycloalkyl include bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, and bicyclo[2.2.2]octyl. Benzocycloalkyl is typified by tetrahydronaphthyl, indanyl, and 1.2-benzocycloheptanyl.
Tumor necrosis factor &agr;, or TNF&agr;, is a cytokine which is released primarily by mononuclear phagocytes in response to a number immunostimulators. When administered to animals or humans, it causes inflammation, fever, cardiovascular effects, hemorrhage, coagulation, and acute phase responses similar to those seen during acute infections and shock states. Excessive or unregulated TNF&agr; production thus has been implicated in a number of disease conditions. These include endotoxemia and/or toxic shock syndrome {Tracey et al.,
Nature
330, 662-664 (1987) and Hinshaw et al.,
Circ. Shock
30, 279-292 (1990)}; cachexia {Dezube et al.,
Lancet,
335 (8690), 662 (1990)} and Adult Respiratory Distress Syndrome where TNF&agr; concentration in excess of 12,000 pg/mL have been detected in pulmonary aspirates from ARDS patients {Millar et al.,
Lancet
2(8665), 712-714 (1989)}. Systemic infusion of recombinant TNF&agr; also resulted in changes typically seen in ARDS {Ferrai-Baliviera et al.,
Arch. Surg.
124(12), 1400-1405 (1989)}.
TNF&agr; appears to be involved in bone resorption diseases, including arthritis. When activated, leukocytes will produce bone-resorption, an activity to which the data suggest TNF&agr; contributes. {Bertolini et al.,
Nature
319, 516-518 (1986) and Johnson et al.,
Endocrinology
124(3), 1424-1427 (1989).} TNF&ag

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