Hydroxamic acid and N-hydroxyurea derivatives and their use

Details Hydroxamic acid and N-hydroxyurea derivatives and their use Hydroxamic acid and N-hydroxyurea derivatives and their use

1993-06-28

2001-09-18

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

N-c doai

C562S623000

Reexamination Certificate

active

06291520

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel hydroxamic acid and N-hydroxyurea derivatives. The compounds of the present invention inhibit the enzyme lipoxygenase, and are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treating inflammatory diseases, allergy and cardiovascular diseases in mammals. This invention further relates to methods of making such compounds.
Arachindonic acid is known to be the biological precursor of several groups of endogenous metabolites, prostaglandins including prostacyclins, thromboxanes and leukotrienes. The first step of arachidonic acid metabolism is the release of arachidonic acid and related unsaturated fatty acids from membrane phospholipids, via the action of phospholipase. Free fatty acids are then metabolized either by cyclooxygenase to produce the prostaglandins and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids which may be further converted to the leukotrienes. Leukotrienes have been implicated in the pathophysiology of inflammatory diseases, including rheumatoid arthritis, gout, asthma, ischemia reperfusion injury, psoriasis and inflammatory bowel disease. Any drug that inhibits lipoxygenase is expected to provide significant new therapy for both acute and chronic inflammatory conditions.
2. Description of the Related Art
Recently several review articles on lipoxygenase inhibitors have been reported (See H. Masamune et al.,
Ann. Rep. Med. Chem.,
24, 71-80 (1989) and B. J. Fitzsimmons et al.,
Leukotrienes and Lipoxygenases,
427-502 (1989).
Compounds of the same general class as the compounds of the present invention are disclosed in EP 279263 A2, EP 196184 A2, JP 63502179 and U.S. Pat. No. 4,822,809.
SUMMARY OF THE INVENTION
The present invention provides novel hydroxamic acid and N-hydroxyurea derivatives of the formula
wherein n is 0 or 1; m is 0 to 3; p is 1 to 6; q is 1 or 2; R
1
is hydrogen, C1 to C4 alkyl, C2 to 4 alkenyl, alkylthioalkyl, alkoxyalkyl or NR
2
R
3
wherein R
2
and R
3
are each independently hydrogen, C1 to C4 alkyl, hydroxy, aryl, or aryl substituted with one or more substituents selected from the group consisting of halo, nitro, cyano, C1 to C12 alkyl, C1 to C12 alkoxy, C1 to C12 halosubstituted alkyl, C1 to C12 hydroxysubstituted alkyl, C1 to C12 alkoxycarbonyl, aminocarbonyl, C1 to C12 alkylaminocarbonyl, di C1 to C12 alkylaminocarbonyl and C1 to C12 alkylsulfonyl, provided that R
2
and R
3
are not both hydroxy; R
4
is hydrogen, a pharmaceutically acceptable cation, aroyl, or C1 to C6 alkoyl; A is C1 to C6 alkylene or C2 to C6 alkenylene; each B is independently hydrogen, halo, nitro, cyano, SH hydroxy C1 to C6 alkyl, C1 to C6 halosubstituted alkyl, C2 to C6 alkenyl, C1 to C6 alkoxy, C1 to C6 thioalkyl, C1 to C12 aminocarbonyl, C1 to C6 alkylaminocarbonyl, di C1 to C6 alkylaminocarbonyl or C1 to C-2 alkoxyalkyl; each Ar is independently phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl or phenoxyphenyl or any of the foregoing substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, —SH, C1 to C12 alkyl, C1 to C12 alkoxy, C1 to C12 halosubstituted alkyl, C1 to C12 hydroxysubstituted alkyl, C1 to C12 alkylamino, di C1 to C12 alkylamino, C1 to C12 alkoxycarbonyl, aminocarbonyl, C1 to C12 alkaminocarbonyl, di C1 to C12 alkylaminocarbonyl and C1 to C12 alkylsulfonyl. The groups Ar, B and the linking group a may be attached at any available position on the ring. Ar and B may be taken together, along with the carbon atoms to which they attached, to form a ring. The dotted line in the chemical formula represents an optional double bond.
This invention also concerns pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and a compound of the invention or a pharmaceutically acceptable salt thereof. This invention further concerns methods of treating inflammatory diseases, allergy and cardiovascular diseases in mammals comprising administration of such compounds or compositions.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
As used herein, the following definitions are used.
“Halo” and “halogen” mean radicals derived from the elements fluorine, chlorine, bromine and iodine.
“Alkyl” means straight or branched saturated hydrocarbon radicals, for example, methyl, ethyl, n-propyl and isopropyl.
“Alkenyl” means straight or branched unsaturated (double bonded) hydrocarbon radicals, for example, ethenyl, 1- or 2-propenyl, 2-methyl-1-propenyl and 1- or 2-butenyl.
“Alkylene” means straight and branched saturated hydrocarbon radicals, for example, —CH
2
—,- —CH(CH
3
)—, —C(CH
3
)
2
—, —CH
2
CH
2
—, —CH
2
CH(CH
3
)—, —CH(C
2
H
5
)—, —C(CH
3
)
2
C(CH
3
)
2
— and —CH
2
CH
2
CH
2
—.
“Alkenylene” means straight or branched unsaturated (double bonded) hydrocarbon radicals, for example, —CH═CH—, —CH═CHCH
2
, —CH═CHCH(CH
3
)—, —C(CH
3
)═CHCH
3
— and —CH
2
CH═CHCH
2
—.
“Alkoxy” means —OR
5
wherein R
5
is an alkyl radical, for example, methoxy, ethoxy, propoxy, isopropoxy and butoxy.
“Alkoxyalkyl” means —R
6
OR
7
wherein R
5
and R
7
are independently alkyl radicals, for example, methoxymethyl, methoxyethyl, ethoxymethyl and ethoxyethyl.
“Thioalkyl” means —SR
8
wherein R
8
is an alkyl radical, for example, methylthio, ethylthio, propylthio and butylthio.
“Alkylamino” means —NHR
9
wherein R
9
is an alkyl radical, for example, methylamino, ethylamino, propylamino and butylamino.
“Dialkyamino” means —NR
9
R
10
wherein R
9
and R
10
are alkyl radicals, for example, dimethylamino, methylethylamino and diethylamino.
“Alkylthioalkyl” means —R
11
SR
12
wherein R
11
and R
12
are independently alkyl radicals, for example, methylthiomethyl, ethylthioethyl and methylthioethyl.
“Alkoyl” means —COR
13
wherein R
13
is an alkyl radical, for example, formyl, acetyl, propionyl, butyryl and isobutyryl.
“Aryl” means aromatic radicals, for example, phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl and phenoxyphenyl.
“Aroyl” means —COR
14
wherein R
14
is an aryl radical, for example, benzoyl and naphthoyl.
“Alkoxycarbonyl” means —C(═O)R
15
wherein R
15
is an alkoxy radical, for example, methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.
“Alkylaminocarbonyl” means —C(═O)NHR
16
wherein R
16
is an alkyl radical, for example, methylaminocarbonyl, ethylaminocarbonyl and propylaminocarbonyl.
“Dialkylaminocarbonyl” means —C(═O)NR
17
R
16
wherein R
17
and R
18
are independently alkyl radicals, for example, dimethylaminocarbonyl, diethylaminocarbonyl and methylethylaminocarbonyl.
“Alkylsulfonyl” means —SO
2
R
19
wherein R
19
is an alkyl radical, for example, methanesulfonyl (mesyl) and ethanesulfonyl.
“Halosubstituted alkyl” means an alkyl radical as described above substituted with one or more halogens, for example, chloromethyl, trifluoromethyl and 2,2,2-trichloroethyl.
“Hydroxysubstituted alkyl” means an alkyl radical as described above substituted with one or more hydroxy radicals, for example, hydroxymethyl, dihydroethyl and trihydroxypropyl.
“Pharmaceutically acceptable cation” means non-toxic cations based on alkali and alkaline earth metals, for example, sodium, lithium, potassium, calcium and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, for example, ammonium, tetramethyl-ammonium, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine and triethylamine.
Methods of Preparation
The compounds of the invention may be prepared by a number of synthetic methods. See, for example, analogous procedures in JP application No. 105048/90. As used in the following reaction schemes, Q is
and A, B, Ar, m, n and p are as defined above. Although in Schemes 1 and 2, below, R
1
is methyl and NH
2
, respectively, compounds wherein R
1
is otherwise, as defined above, may be prepared in a similar manner.
In one embodime

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