Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-11-22
2001-07-24
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S238200, C514S357000, C514S603000, C514S604000, C514S824000, C514S863000, C544S149000, C544S160000, C546S282100, C546S332000, C549S419000, C556S419000, C564S081000
Reexamination Certificate
active
06265446
ABSTRACT:
BACKGROUND OF THE INVENTION
Release of such cytokines as tumor necrosis factor &agr; (TNF-&agr;) and transforming growth factor a (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 (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 novel 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 heterocyclyl or NR
5
R
6
;
R
3
represents hydrogen, lower alkyl, halo-lower alkyl, cyano-lower alkyl, hydroxy-lower alkyl, amino-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, heteroaryl or aryl-lower alkyl;
R
4
represents lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl or a grouping of the formula —Z-aryl, —Z-heterocyclyl or —(CH
2
)
n
—CH═CR
7
R
8
;
R
5
and R
6
each independently represent hydrogen or lower alkyl;
R
7
and R
8
each independently represent hydrogen or lower alkyl or R
7
and R
8
together represent lower alkylene in which one CH
2
group is optionally replaced by a hetero atom;
X and Z each represent a spacer group; and
n stands for 0, 1 or 2;
as well as mixtures of said compounds with one or more of their corresponding optical isomers and pharmaceutically acceptable salts of said compounds or said mixtures.
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
, haemorrhaue
20, 21
and sepsis
22
. Therefore the compounds of formula I are useful in treating the TNF-(X dependent cellular processes associated with these diseases.
The present invention is further directed the medicaments comprising a compound as described above or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier material and to methods for making such medicaments.
The present invention is also directed the novel intermediates useful in the synthesis of the above described compounds.
Furthermore, the present invention is directed to a process for preparing compounds of formula (I).
In another aspect the present invention is directed to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of illnesses. In yet another aspect the present invention is directed to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation or a medicament for the treatment of inflammatory and autoimmune diseases, osteoarthritis, respiratory diseases, tumors, cachexia, cardiovascular diseases, fever, haemorrhage and sepsis.
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 chloro-methyl, 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” means an alkenyl group containing from 2 to 7 carbon atoms, e.g. allyl, vinyl and butenyl.
The term “lower alkynyl” means an alkynyl group containing from 2 to 7 carbon atoms, e.g. propargyl 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-dimethoxy-phenethyl and the like are typical examples of aryl-lower alkyl 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 by up to four substituents, e.g. halogen, lower alkyl, lower alkoxy and/or oxo 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, hexahydroazepinyl, tetrahydropyranyl, tetrahydrothiopyranyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, oxetanyl, imidazolidinyl, dioxolanyl, pyrrolyl, pyridyl, pyrimidinyl, benzofuranyl, benzothienyl, benzthiazolyl, 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.
The spacer group denoted by X can be, for example, a group of the formula —(CH
2
)
1-5
— or —(CH
2
)
l
—Y—(CH
2
)
m
— in which l and m each independently stand for 0, 1 or 2 and Y represents arylene, lower cycloalkylene or heterocyclylene.
The spacer group denoted by Z can be, for example, a group of the formula —(CH
2
)
p
—W—(CH
2
)
q
— in which p and q each independently stand for 0, 1, 2 or 3 and W is absent or, preferably, represents
Broadhurst Michael John
Johnson William Henry
Walter Daryl Simon
Epstein William H.
Hoffmann-La Roche Inc..
Johnston George W.
Kreisler Lewis J.
O'Sullivan Peter
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