Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1998-06-16
2001-05-22
Lee, Howard C. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S601000, C514S625000, C514S837000, C514S861000, C514S863000, C514S885000, C514S903000, C564S081000, C564S095000, C564S148000, C564S151000, C564S154000
Reexamination Certificate
active
06235787
ABSTRACT:
BACKGROUND OF THE INVENTION
Release of such cytokines as tumor necrosis factor &agr;(TNF-&agr;) and transforming growth factor &agr;(TGF-&agr;) can cause adverse reactions ranging from fever to sepsis. Many of these reactions are related to inflammation or autoinmuune conditions, such as psoriasis and arthritis.
Hydroxamic acid derivatives are known to have some inhibitory effect against the release of certain cytokines, however they also inhibit matrix metalloproteinase enzymes (MMPs) 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; release which do not have these side effects. It has been discovered that, 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 general formula:
wherein
Y is CO or SO
2
;
R
1
is lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl or aryl-lower alkyl;
R
2
is lower alkyl, halo-lower alkyl, aryl-lower alky, aryl-lower alkenyl or aryl when Y is SO
2
and is lower alkyl, halo-lower alkyl, lower alkoxy, lower alkoxycarbonyl, acyl, lower cycloalkyl, aryl, aryl-lower alky, aryl-lower alkoxy or NR
5
R
6
when Y is CO; and
R
3
is hydrogen, lower alkyl optionally substituted by cyano, amino, hydroxy, lower alkoxy, lower alkoxycarbonyl, heterocyclyl or heterocyclylcarbonyl, lower alkenyl, lower alkynyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl-lower alkyl, aryl-lower alkenyl, aryl or heterocyclyl; or
R
2
and R
3
together form the residue of a 5-, 6- or 7-membered cyclic amide, cyclic imide, cyclic sulphonamide or cyclic urethane group;
R
4
is lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl or a group of the formula X-aryl, X-heteroaryl or —(CH
2
)
1-2
—CH═CR
7
R
8
;
X is a spacer group;
R
5
and R
6
each individually are hydrogen, lower alkyl or aryl-lower alkyl; and
R
7
and R
8
together represent a lower alkylene group in which one methylene group is optionally replaced by a hetero atom;
and pharmaceutically acceptable salts thereof.
The hydrazine derivatives provided by the present invention are inhibitors of TNF-&agr; and TGF-&agr; release from cells. They also inhibit the proliferation of keratinocytes. Accordingly, the present hydrazine derivatives can be used as medicaments for the treatment of conditions related to release of these cytokines, especially in inflammation, fever, haemorrhage, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis and psoriasis.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “lower alkyl”, alone or in combination as in e.g. “halo-lower alkyl” and “lower cycloalkyl-lower alkyl”, means a straight-chain or branched-chain alkyl group containing up to 7, 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. Trifluoromethyl is an example of a halo-lower alkyl group.
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, and the term “lower alkynyl” means an alkynyl group containing from 2 to 7 carbon atoms, e.g. propargyl or butynyl.
The term “lower alkylene” means an alkylene group containing from 2 to 6 carbon atoms, e.g. dimethylene, trimethylene, tetramethylene etc. Thus, R
7
and R
8
together with the carbon atom to which they are attached can represent, for example, a cyclopentane, cyclohexane or tetrahydropyranyl ring.
The term “acyl” denotes an acyl group derived from a lower alkanecarboxylic acid, i.e. an alkanecarboxylic acid containing up to 6 carbon atoms, or from an aromatic carboxylic acid. Examples of such acyl groups are acetyl, propionyl, butyryl, isobutyryl, pivaloyl, benzoyl, p-chlorobenzoyl, and the like.
The term “aryl” 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 and benzyloxy, 4-chlorobenzyloxy and 4-nitro-benzyloxy 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” means a 4-, 5- or 6-membered saturated or partially unsaturated or 5- or 6-membered aromatic heterocyclic group 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 which is optionally substituted by e.g. halogen, lower alkyl, lower alkoxy and/or oxo and/or optionally benz-fused. Examples of heterocyclyl groups are pyrrolidinyl, pyrrolinyl, pyrazolinyl, piperidinyl, morpholinyl, thiamorpholinyl, 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 cyclic amide, imide, sulphonamide or urethane group formed by R
2
, R
3
and the atoms to which they are attached, i.e. the C or S atom of Y and, respectively, the N atom, can be, for example, a group of formulae (a)-(g) hereinafter in which n stands for 3, 4 or 5 and R
a
and R
b
together form the reminder of an aromatic or cycloalkane ring:
Preferred spacer groups denoted by X are groups of the formulae —(CH
2
)
1-5
—, —CH
2
—CH═CH—, —CH
2
—C≡C—, —CH
2
NHCO—, —(CH
2
)
1
or
2
NHCONH—, —(CH
2
)
1-5
—S—, especially —CH
2
S—, —CH
2
NHSO
2
—, —CH
2
NHCH
2
—, —(CH
2
)
1-5
—O—, —O—(CH
2
)
1-5
— and —S—.
The compounds of formula I form pharmaceutically acceptable salts with bases such as alkali metal hydroxides, e.g. sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides, e.g. calcium hydroxide, barium hydroxide and magnesium hydroxide, and the like. Those compounds of formula I which are basic can form pharmaceutically acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric acid and hydrobromic acid, sulphuric acid, nitric acid and phosphoric acid, and with organic acids, e.g. with acetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid methanesulphonic acid and p-toluenesulphonic acid. Such salts are part of this invention. Thus each compound described below includes its pharmaceutically acceptable s
Broadhurst Michael John
Johnson William Henry
Walter Daryl Simon
Hoffmann-La Roche Inc.
Johnston George W.
Lee Howard C.
Tramaloni Dennis P.
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