Hydroxamic acid derivatives

Details Hydroxamic acid derivatives Hydroxamic acid derivatives

2001-10-09

2002-12-31

Kumar, Shailendra (Department: 1621)

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

Organic compounds

Hydroxamic acids, chalcogen analogs or salts thereof

C514S238200, C514S352000, C514S419000, C514S575000, C544S168000, C546S309000, C548S491000, C562S623000

Reexamination Certificate

active

06500983

ABSTRACT:

This invention relates to novel hydroxamic acid compounds which are useful as pharmaceuticals, e.g., in inhibiting matrix metalloproteinases such as collagenase, and in inhibiting TNF production, particularly for treatment of diseases or conditions mediated by over-production of or over-responsiveness to TNF&agr;.
Tumor necrosis factor (TNF) is a cytokine which is produced initially as a membrane-bound 28 kD precursor. It is then cleaved by an enzyme (TNF convertase) and released as a soluble, active 17 kD form. Soluble TNF exists in at least two forms, TNF&agr; and TNF&bgr;, of which TNF&agr; appears to be the more significant clinically. TNF&agr; is believed to mediate inflammation and other conditions associated with septic shock or acute infections. Long term overstimulation by TNF&agr; is believed to play a role in autoimmune and chronic inflammatory conditions, such as arthritis, multiple sclerosis, and the like.
It has been shown that certain matrix metalloproteinase inhibitors of the hydroxamic acid class, in particular 3-imino-4-oxo-heptane-1,7-dioic acid (7-N-hydroxy) diamides (which are optionally further 1-N-, 2-, 5-, and 6-substituted) are capable of mediating TFN&agr; production, possibly by inhibiting TNF convertase. Known representatives of this class of compounds are summarized and described, e.g., in WO 94/10990.
It has now surprisingly been discovered that a new class of hydroxamic acid derivatives (“Novel Compounds”) are potent TNF&agr; suppressors and have advantageous pharmaceutical properties, in particular, oral bioavailability.
The Novel Compounds are 3-imino-4-oxo-6-(oxymethyl)-heptane-1,7-dioic acid (7-N-hydroxy) diamides. Suitably, the 6-oxymethyl substituent is of formula II below, e.g., hydroxymethyl or mono- or polyalkoxymethyl. The Novel Compounds may have further substitutions at the 1-N-, 2-, and 5-positions as known in the art, e.g., as described in WO 94/10990, or as further described herein. For example, the Novel Compounds may be 1-N substituted with methyl, pyridyl, or a substituent of formula X—Y— or X′—Y— as described below, e.g., 3-imino-4-oxo-6-(oxymethyl)-heptane-1,7-dioic acid (1-N-morpholinocarbonylalkyl, 7-N-hydroxy) diamide, and may be in free or pharmaceutically acceptable salt form.
A particularly preferred class of Novel Compounds are 3-imino-4-oxo-5-aryl-6-(oxymethyl)-heptane-1,7-dioic acid (7-N-hydroxy) diamides. The 5-aryl substituent may be as further described herein, e.g. wherein the 5-aryl substituent is phenyl optionally substituted, conveniently at the 4-position, e.g. by hydroxy-, C
1-6
alkyl-, C
1-6
alkoxy-, amino-, halo- or cyano-. Such 5-aryl substituted Novel Compounds may be in free or pharmaceutically acceptable salt form.
Preferably, the Novel Compounds are of Formula I
wherein
R
1
is a substituent of Formula II:
A—(O—(CR
5
H)
n
)
m
—O—CH
2
—  Formula II
 wherein
n is 1, 2, 3 or 4, preferably 2;
m is 0, 1, 2 or 3;
each R
5
is
independently H, C
1-6
(optionally hydroxy-, C
1-6
alkoxy-, amino-, C
1-6
alkylamino-, thiol-, C
1-6
alkylmercapto- or protected hydroxy, amino or thiol substituted) alkyl, C
2-6
alkenyl, C
6-14
(optionally hydroxy-, C
1-6
alkoxy-, amino-, C
1-6
alkylamino-, halo- or cyano- substituted) aryl, or C
6-14
(aryl) C
1-6
alkyl; preferably H, phenyl, benzyl or C
1-5
alkyl;
A is hydrogen, C
1-10
alkyl, C
6-14
aryl, C
6-14
aryl, (C
1-6
alkyl), (C
6-14
aryl)carbonyl, or (C
1-10
alkyl)carbonyl; preferably hydrogen, C
1-6
alkyl (e.g., methyl or cyclohexyl), phenyl or benzyl;
R
2
is C
2-12
alkyl, C
3-12
alkenyl, C
3-7
(optionally hydroxy-, C
1-6
alkoxy-, amino-, or C
1-6
alkylamino- substituted) cycloalkyl, C
5-14
aryl, or C
5-14
aryl(C
1-6
alkyl), wherein aryl groups are optionally substituted by hydroxy-, C
1-6
alkyl-, C
1-6
alkoxy-, amino-, halo- or cyano-; preferably phenyl, 4-methylphenyl, 4-methoxyphenyl, cyclohexyl or isobutyl;
R
3
is C
1-10
(optionally hydroxy- or C
1-6
alkoxy- amino-, C
1-6
alkylamino-, thiol-, C
1-6
alkylmercapto- or protected hydroxy-, amino- or thiol- substituted) alkyl (e.g., t-butyl, or cyclohexylmethyl), C
6-14
(optionally hydroxy-, C
6-14
aryloxy-, or C
1-6
alkoxy-, amino-, C
1-6
alkylamino-, halo-, or cyano- substituted) aryl (e.g., benzyl, p-methoxybenzyl, p-benzyloxybenzyl), or indolylmethyl (e.g., 2-indolylmethyl); preferably benzyl or t-butyl;
R
4
is methyl, pyridyl, or a substituent of formula X—Y— wherein X is morpholino, pyridyl or aryl (preferably morpholino), and Y is C
1-12
alkylene in which up to four of the methylene (—CH
2
—) units are optionally replaced with —CO—, —NH—, —SO
2
— or —O—; for example methyl, 2-pyridyl, morpholinocarbonylmethyl, 5-morpholino)pentyl, or 5-(morpholinocarbonyl)pentyl.
“alkyl” includes linear, cyclic, or branched alkyl; and
“aryl” refers to an monovalent aromatic radical containing one or two aromatic rings, e.g., phenyl, benzyl, or tolyl, and includes heteroaryl containing one or more hetero atoms, e.g. N, O or S.
Halo or halogen as used herein refers to F, Cl, Br or I unless otherwise indicated.
Conveniently R
1
is a substituent of formula II′
A—(O—(CH
2
)
n
)
m
—O—CH
2
—  Formula II′
wherein A, n and m are as defined above.
In an alternative particular embodiment R
1
is a substituent of formula II″
A—O—(CHR
5
—(CH
2
)
n
)
m′
—O—CH
2
—  Formula II″
wherein A, n and R
5
are as defined above and m′ is 0, 1 or 2.
When R
4
of formula I is a substituent of formula X—Y—, it is preferably a substituent of formula X′—Y— wherein X′ is morpholino and Y is as defined above.
In particular embodiments the invention provides Novel Compounds of formula I in which independently:
n of Formula II is 3 or 4; or
R
5
of Formula II is not H; or
R
2
is C
7-12
alkyl, C
3-12
alkenyl, C
3-7
(optionally hydroxy-, C
1-6
alkoxy-, amino-, or C
1-6
alkylamino- substituted) cycloalkyl, C
5-14
aryl, or C
5-14
aryl(C
1-6
alkyl), wherein aryl groups are optionally substituted by hydroxy-, C
1-6
alkyl-, C
1-6
alkoxy-, amino-, halo- or cyano-; preferably phenyl, 4-methylphenyl, 4-methoxyphenyl or cyclohexyl; or R
3
is C
1-10
(amino-, C
1-6
alkylamino-, thiol-, C
1-6
alkylmercapto- or protected hydroxy-, amino- or thiol- substituted)alkyl, C
6-14
(amino-, C
1-6
alkylamino-, halo-, or cyano- substituted)aryl; or
any aryl group thereof is heteroaryl containing one or more hetero atoms, e.g. N, O or S.
In further particular embodiments the invention provides Novel Compounds of formula I′
in which
R
1
′ is a substituent of Formula II′″:
A′—(O—(CH
2
)
n′
)
m′
—O—CH
2
—  Formula II′″
 such that
n′ is an integer one or two, preferably two;
m′ is an integer zero, one, two, or three;
A′ is hydrogen, C
6-14
aryl, C
1-10
alkyl, (C
6-14
aryl)carbonyl, or (C
1-10
alkyl)carbonyl, (preferably C
1-6
alkyl, e.g., methyl or cyclohexyl);
R
2
′ is C
2-6
alkyl, preferably isobutyl;
R
3
′ is C
1-10
(optionally hydroxy- or C
1-6
alkoxy-substituted) alkyl (e.g., t-butyl, or cyclohexylmethyl), C
6-14
(optionally hydroxy-, C
6-14
aryloxy-, or C
1-6
alkoxy-substituted) aryl (e.g., benzyl, p-methoxybenzyl, p-benzyloxybenzyl), or indolylmethyl (e.g., 2-indolylmethyl); preferably benzyl or t-butyl;
R
4
′ is methyl, pyridyl, or a substituent of formula X—Y— wherein X is morpholino, pyridyl or aryl (preferably morpholino), and Y is C
1-12
alkylene in which up to four of the methylene (—CH
2
—) units are optionally replaced with —CO—, —NH—, —SO
2
— or —O—; for example methyl, 2-pyridyl, morpholinocarbonylmethyl, 5-(morpholino)pentyl, or 5-(morpholinocarbonyl)pentyl;
Preferred Novel Compounds in which R
2
is aryl are compounds in which R
1
is of formula II′ as defined above and R
2
is phenyl, 4-methylphenyl or 4-methoxyphenyl.
An especially preferred group of compounds of Formula I are compounds wherein:
(i) R
1
is of formula II′ or II″ (preferably formula II′) and A of formula II is hydrogen, C
1-6
alk

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