Cyclic hydrazine derivatives

Details Cyclic hydrazine derivatives Cyclic hydrazine derivatives

1999-12-09

2001-08-28

Shah, Mukund J. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S318100, C548S316400, C548S300100

Reexamination Certificate

active

06281363

ABSTRACT:

BACKGROUND OF THE INVENTION
Release of such cytokines as tumor necrosis factor &agr; (TNF-&agr;) and transforming growth factor &agr; (TNF-&agr;) can cause adverse reactions ranging from psoriasis to sepsis. Many of these reactions are related to inflammanation or autoimmune conditions, such as psoriasis and arthritis.
Hydroxamic acid derivatives are known to have some inhibitory effect against certain cytokines, however they also inhibit matrix metalloproteinase enzymes (MMPs) such as collagenases, stromelysins, and gelatinases, leading to undesirable side effects. Thus it is desirable to find compounds capable of inhibiting TNF-&agr; and TGF-&agr; which do not have these side effects. In contrast to structurally related hydroxamic acid derivatives, the hydrazine derivatives provided by the present invention show only weak inhibitory activity against the matrix metalloproteinase (MMP) family of enzymes, such as collagenases, stromelysins and gelatinases.
SUMMARY OF THE INVENTION
1. This invention provides a hydrazine derivative, being a compound of the formula
wherein
W is O, S, CO, NR
5
, (CR
3
R
4
)
m
, or CR
11
;
X is CO, NR
6
, (CH
2
)
n
, CR
12
or CHR
13
;
Y is CO, NR
7
, (CH
2
)
p
, or CHR
14
;
Z is CO, CS, SO
2
, or CH
2
;
m is 0 or 1;
n and p are each independently 0, 1 or 2;
R
1
is unsubstituted lower alkyl, unsubstituted lower alkenyl, unsubstituted lower cycloalkyl, unsubstituted lower cycloalkyl-lower alkyl, unsubstituted or substituted aryl, or aryl-lower alkyl in which the aryl is unsubstituted or substituted and the lower alkyl is unsubstituted;
R
2
is unsubstituted lower alkyl, unsubstituted lower alkenyl, unsubstituted lower cycloalkyl, unsubstituted lower cycloalkyl-lower alkyl, —V-aryl in which the aryl is unsubstituted or substituted, —V-heterocyclyl in which the heterocyclyl is unsubstituted or substituted, or —(CH
2
)
q
—CH═CR
8
R
9
;
R
3
, R
4
, R
5
, R
6
and R
7
are each independently hydrogen, unsubstituted or substituted lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl in which the lower alkyl is unsubstituted and the cycloalkyl is unsubstituted, unsubstituted or substituted aryl, aryl-lower alkyl in which the aryl is unsubstituted or substituted and the lower alkyl is unsubstituted, unsubstituted or substituted heterocyclyl or heterocyclyl-lower alkyl in which the the heterocyclyl is unsubstituted or substituted and the lower alkyl is unsubstituted; or R
3
and R
4
together with the carbon atom to which they are attached form a saturated carbocyclic ring having from 3 to 8 ring atoms in which zero or one ring atom is a heteroatom selected from the groups consisting of N, O and S wherein the ring nitrogen is unsubstituted or substituted; or R
5
and R
6
or R
5
and R
7
together with the nitrogen atoms to which they are attached form a saturated carbocyclic ring having from 3 to 8 ring atoms; or R
11
and R
12
together with the sp
2
carbon atoms to which they are attached form a fused unsubstituted lower cycloalkenyl, unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl ring; or R
5
with either R
13
or R
14
together are lower alkylene in which zero or one CH
2
of the lower alkylene is replaced by a heteroatom selected from the group consisting of N, O and S wherein the N is unsubstituted or substituted; or either R
6
or R
7
with either R
3
or R
4
together are lower alkylene in which zero or one CH
2
of the lower alkylene is replaced by a heteroatom selected from the group consisting of N, O and S wherein the N is unsubstituted or substituted;
V is —(CH
2
)
r
—U—(CH
2
)
s
— in which r and s are each independently 0, 1, 2 or 3 and wherein U is absent or is —CH═CH—, —C≡C—, —S—, —O—, —NH—, —NHCO—, —CONH—, —SO
2
—, —NHSO
2
—, —SO
2
NH—, —NHCONH— or —NHSO
2
NH—;
R
8
and R
9
together are lower alkylene in which zero or one CH
2
of the lower alkylene is replaced by a heteroatom selected from the group consisting of N,O and S wherein the N is unsubstituted or substituted; and q is 1 or2;
wherein (i) at least one of W, X and Y is one of the heteroatoms previously indicated for these substituents or CO, (ii) if W is O, Z must be CO or SO
2
or CS; (iii) W, X, Y and Z are not all CO; (iv) W, X and Y are not all NR
5
, NR
6
and NR
7
, respectively; and (v) when either W is CR
11
, X is CR
12
, or the bond between W and X is a double bond or an aromatic bond, then W is CR
11
, X is CR
12
and the bond between W and X is a double bond or an aromatic bond;
or a mixture containing the compound and one or more optical isomers thereof, or a pharmaceutically acceptable salt of said compound or said mixture.
The hydrazine derivatives provided by the present invention are inhibitors of tumour necrosis factor alpha (TNF-&agr;) release from cells. TNF-&agr; has been associated with various cellular processes including inflammatory and cytotoxic processes. In particular TNF-&agr; has been associated with inflammatory and autoimmune diseases (such as rheumatoid arthritis
1
, inflammatory bowel disease
2
, psoriasis
16,17
), osteoarthritis
5,6
, respiratory diseases (such as chronic obstructive pulmonary disease
7,8
and asthma
8,9
), tumor growth and angiogenesis
10
, cachexia
11,12
, cardiovascular diseases (such as congestive heart failure
13,14
), dermatological diseases (such as graft-versus-host-disease
15
and), fever
18,19
, haemorrhage
20,21
and sepsis
22
. Therefore the compounds of formula I are useful in treating the TNF-&agr; dependent cellular processes associated with these diseases.
DETAILED DESCRIPTION OF THE INVENTION
2. In a more specific embodiment of the hydrazine derivative described above, the compound has the formula
wherein
W is O, S, CO, NR
5
or (CR
3
R
4
)
m
;
X is NR
6
or —(CH
2
)
n
—;
Y is CO, NR
7
or —(CH
2
)
p
—;
Z is CO, SO
2
or CH
2
;
m is 0 or 1;
n and p are each independently 0, 1 or 2;
R
1
is unsubstituted lower alkyl, lower alkenyl, lower cycloalkyl, unsubstituted lower cycloalkyl-lower alkyl, unsubstituted or substituted aryl, or aryl-lower alkyl in which the aryl is unsubstituted or substituted and the alkyl is unsubstituted;
R
2
is unsubstituted lower alkyl, lower alkenyl, lower cycloalkyl, unsubstituted lower cycloalkyl-lower alkyl, —V-aryl in which the aryl is unsubstituted or substituted, —V-heterocyclyl in which the heterocyclyl is unsubstituted or substituted or —(CH
2
)
q
—CH═CR
8
R
9
;
R
3
, R
4
, R
5
, R
6
and R
7
are each independently hydrogen, unsubstituted lower alkyl, lower alkenyl, lower cycloalkyl, unsubstituted lower cycloalkyl-lower alkyl, unsubstituted or substituted aryl, aryl-lower alkyl in which the aryl is unsubstituted or substituted and the alkyl is unsubstituted, unsubstituted or substituted heterocyclyl, or heterocyclyl-lower alkyl in which the heterocyclyl is unsubstituted or substituted and the lower alkyl is unsubstituted; or R
3
and R
4
together with the carbon atom to which they are attached form a saturated carbocyclic ring having from 3 to 8 ring atoms in which zero or one ring atom is a heteroatom selected from the group consisting of N, O and S wherein the ring nitrogen is unsubstituted or substituted; or R
5
and R
6
or R
5
and R
7
together with the nitrogen atoms to which they are attached form a saturated carbocyclic ring having from 3 to 8 ring atoms;
V is —(CH
2
)
r
—U—(CH
2
)
s
— in which r and s are each independently 0, 1, 2 or 3 and wherein U is absent or is —CH═CH—, —C≡C—, —S—, —O—, —NH—, —NHCO—, —CONH—, —SO
2
—, —NHSO
2
—, —SO
2
NH—, —NHCONH— or —NHSO
2
NH—;
R
8
and R
9
together are lower alkylene in which zero or one CH
2
is replaced by a heteroatom selected from the group consisting of N, O and S wherein the N is unsubstituted or substituted; and
q is 1 or 2;
wherein (i) at least one of W, X and Y is one of the heteroatoms previously indicated for these substituents or CO and (ii) if W is O Z must be CO or SO
2
and (iii) W, X and Y are not all NR
5
, NR
6
and NR
7
, respectively.
As used herein, the term “lower alkyl”, alone or in combination as in “lower cycloalkyl-

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