Compounds as inhibitor of tumor necrosis factor alpha release

Details Compounds as inhibitor of tumor necrosis factor alpha release Compounds as inhibitor of tumor necrosis factor alpha release

1999-06-14

2001-05-29

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S359000, C514S396000, C514S482000, C546S231000, C548S261000, C548S335500, C564S151000, C564S153000

Reexamination Certificate

active

06239151

ABSTRACT:

BACKGROUND OF THE INVENTION
Release of such cytokines as tumor necrosis factor a (TNF-&agr;) and transforming growth factor &agr; (TGF-&agr;) can cause adverse reactions ranging from psoriasis to sepsis. Many of these reactions are related to inflammation 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 (MPPs) such as collagenases, stromolysins, 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
The hydrazine derivatives provided by the present invention are compounds of the formula
wherein
R
1
represents lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl or aryl-lower alkyl;
R
2
represents an acyl group derived from an &agr;-, &bgr;-, &ggr;- or &dgr;-(amino, hydroxy or thiol)carboxylic acid in which the amino, hydroxy or thiol group is optionally lower alkylated or the amino group is optionally acylated, sulphonylated or amidated and in which any functional group present in a side-chain is optionally protected, or a group of the formula Het(CH
2
)
m
CO—;
R
3
represents hydrogen, lower alkyl, halo-lower alkyl, cyano-lower alkyl, amino-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, lower cycloalkyl-lower alkyl, aryl-lower alkyl, heterocyclyl-lower alkyl, heterocyclylcarbonyl-lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl-lower alkenyl, aryl or heterocyclyl;
R
4
represents lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl or a grouping of the formula X-aryl, X-heteroaryl or —(CH
2
)
n
—CH═CR
5
R
6
;
R
5
and R
6
together represent lower alkylene in which one CH
2
group is optionally replaced by a hetero atom;
Het represents heterocyclyl;
X represents a spacer group;
m stands for 0, 1, 2, 3 or 4; and
n stands for 1 or 2;
and pharmaceutically acceptable salts thereof.
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 inflamrnatory 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 asthmas
8,9
), tumour 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
As used herein, the term “lower alkyl”, alone or in combination as in, for example, “halo-lower alkyl” or “lower cycloalkyl-lower alkyl”, means a straight-chain or branched-chain alkyl group containing up to 8, preferably up to 4, carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert-butyl, n-pentyl and n-hexyl.
The term “halo-lower alkyl” means a lower alkyl group as defined earlier which carries one or more halogen atoms. Examples of halo-lower alkyl groups are chloromethyl, trifluoromethyl and 2,2,2-trifluoroethyl.
The term “lower alkoxy”, alone or in combination as in “lower alkoxycarbonyl”, means a lower alkyl group as defined above which is bonded via an oxygen atom, e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Methoxycarbonyl, ethoxycarbonyl and the like are examples of lower alkoxycarbonyl groups.
The term “lower cycloalkyl”, alone or in combination as in “lower cycloalkyl-lower alkyl”, means a cycloalkyl group containing 3 to 7 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cyclopropylmethyl, 2-cyclobutyl-ethyl and 3-cyclohexyl-propyl are examples of lower cycloalkyl-lower alkyl groups.
The term “lower alkenyl”, alone or in combination as in “aryl-lower alkenyl”, means an alkenyl group containing from 2 to 7 carbon atoms, e.g. allyl, vinyl and butenyl.
The term “lower alkylene” means an alkylene group containing from 2 to 6 carbon atoms, e.g. dimethylene, trimethylene, tetramethylene etc. Thus, R
5
and R
6
together with the carbon atom to which they are attached can represent, for example, a cyclopentane or cyclohexane ring. One CH
2
group may optionally be replaced by a heteroatom selected from N(H), S, or O wherein the hydrogen in the N(H) group may optionally be substituted by a lower alkyl group. For example, where R
5
and R
6
together with the carbon atom to which they are attached form a tetrahydropyrane ring.
The term “lower alkynyl” means an alkynyl group containing from 2 to 7 carbon atoms, e.g. propanyl or butynyl.
The term “aryl”, alone or in combination as in “aryl-lower alkyl”, means phenyl or naphthyl optionally substituted by halogen, i.e. fluorine, chlorine, bromine or iodine, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy, lower alkoxycarbonyl, nitro, phenyl or the like, e.g. phenyl, 1-naphthyl, 2-methylphenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 4-nitrophenyl and 4-methoxycarbonylphenyl. Benzyl, 4-chlorobenzyl, 4-bromobenzyl, 3-hydroxybenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 2-phenylethyl, 3,4-dimethoxyphenethyl and the like are typical examples of aryl-lower alkyl groups and benzyloxy, 4-chlorobenzyloxy and 4-nitrobenzyloxy are typical examples of aryl-lower alkoxy groups. 2-Phenylvinyl and 3-phenylallyl can be mentioned as examples of aryl-lower alkenyl groups.
The term “heterocyclyl”, alone or in combination as in “heterocyclyl-lower alkyl”, means a 4-, 5-, 6- or 7-membered saturated or partially unsaturated or 5- or 6-membered aromatic heterocyclic ring which is bonded via a C atom or secondary N atom (i.e. —NH—), which contains one or more hetero atoms selected from nitrogen, sulphur and oxygen and/or a SO or SO
2
group and which is optionally substituted at any ring atom by up to four substituents, e.g. halogen, lower alkyl, lower alkoxy, oxo, thioxo and/or imino, and/or optionally benz-fused. Preferably the heterocyclyl group contains from 1 to 4 heteroatoms. Examples of such heterocyclyl groups are pyrrolidinyl, pyrrolinyl, pyrazolinyl, piperidinyl, N-methylpiperidinyl, morpholinyl, thiamorpholinyl, thiamorpholinyl S,S-dioxide, tetrahydropyranyl, tetrahydrothiopyranyl, hexahydroazepinyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, oxetanyl, imidazolidinyl, dioxolanyl, pyrrolyl, pyridyl, pyrimidinyl, benzofuranyl, benzothienyl, benzthiazolyl, 1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinyl, 2-thioxo-4-oxo-5-thiazolidinyl, 1-methyl-3-pyrrolyl, indolyl, isoindolyl, e.g. phthalimido, quinolyl, and isoquinolyl.
The term “heterocyclylcarbonyl” means a heterocyclyl group as previously defined which is bonded to C(O) via a secondary N atom. Morpholinocarbonyl is a typical example of such a heterocyclylcarbonyl group.
The term “heteroaryl” means an aromatic heterocyclic group within the definition of “heterocyclyl”.
The term “halo” means fluoro, chloro, bromo or iodo unless specifically indicated to the contrary.
An acyl group R
2
can be derived from a L-, D- or racemic amino-, hydroxy- or thiolcarboxylic acid when such an acid contains a chiral centre. Thus, R
2
can represent an acyl group derived from an &agr;-aminocarboxylic acid such as glycine, L- or D-alanine, L- or D-valine, L- or D-leucine, L- or D-lysine, L- or D-serine, L- o

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