Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-09
2002-09-17
Chang, Ceila (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S319100, C560S122000
Reexamination Certificate
active
06452010
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to an improved process for the preparation of a hydroxamic acid derivative from the corresponding carboxylic acid.
Hydroxamic acid derivatives of certain carboxylic acids have been recognized as inhibitors of matrix metalloproteinases (MMPs) which are a family of proteases (enzymes) involved in the degradation and remodeling of connective tissues. Excessive degradation of extracellular matrix by MMPs is implicated in the pathogenesis of many diseases, including rheumatoid arthritis, osteoarthritis, multiple sclerosis, bone resorptive diseases (such as osteoporosis), chronic obstructive pulmonary disease, restenosis, cerebral hemorrhaging associated with stroke, periodontal disease, aberrant angiogenesis, tumor invasion and metastasis, corneal and gastric ulceration, ulceration of skin, aneurysmal disease, and in complications of diabetes. MMP inhibition is, therefore, recognized as a good target for therapeutic intervention of this type of diseases.
Current synthetic methods of introducing the hydroxylamine group in carboxylic acids and in particular such MMP inhibitors employ the reaction with a hydroxyl-ammonium salt derived from an inorganic acid such as HCl, H
2
SO
4
or H
3
PO
4
etc. such as hydroxylammonium chloride, hydroxylammonium sulfate or hydroxylammonium phosphate (see e.g. EP 0 818 442 A2 or WO 96/00214 for such inhibitors and methods for making them, especially with regard to the introduction of the hydroxylamine group). However, these reagents have also drawbacks regarding side reactions, especially with sterically hindered or sensitive carboxylic acids, which reduce the yield of the compound obtained.
To overcome these problems, the reaction is then performed by employing O-derivatized hydroxylamine reagents like benzylhydroxylammonium chloride, O-tetrahydropyranyl-hydroxylamine or O-trimethylsilyl-hydroxylamine. All these reagents are O-protected reagents which have to be prepared separately and which require subsequent deprotection to yield the free hydroxylamine group.
Accordingly, there is still a need for providing an improved process for the preparation of hydroxamic acid derivatives in general and for those suitable as enzyme inhibitors in particular. This problem has been solved by the present invention.
SUMMARY OF THE INVENTION
The present invention provides a process for the manufacture of a hydroxamic acid derivative from the corresponding carboxylic acid, characterized in that the carboxyl group is reacted with a hydroxylammonium salt of a carboxylic acid in a suitable solvent. The “corresponding carboxylic acid” means the carboxylic acid precursor which is converted into the hydroxamic acid derivative.
It has unexpectedly been found that the hydroxylamine group can also be introduced by using a hydroxylammonium salt of an organic acid as a reagent. These reagents can advantageously be used as effective reagents to make the hydroxamic acid from the corresponding carboxylic acid, especially when the corresponding carboxylic acid is sterically hindered or very sensitive to basic conditions. Preferably, the carboxylic acid used in the hydroxylammonium salt reagent is different from the corresponding carboxylic acid it is reacted with especially if the corresponding carboxylic acid is difficult to obtain compared to acids useful in the reagent.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions are used in the description. “Halogen” is to be understood hereinafter as chlorine, bromine and iodine. “Alkyl” signifies a straight-chain or branched alkyl group with 1 to 8C atoms, preferably 1-6C atoms, such e.g. methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and tert.butyl. “Alkoxy” means an Alkyl-O— group wherein one hydrogen has been replaced by an oxygen atom. “Aryl”, alone or in combination, means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl, 1-naphthyl, 2-naphthyl, and the like. “Cycloalkyl”, alone or in combination, means a saturated monocyclic ring of 3 to 7 carbon atoms, e.g., cyclopentyl, cyclohexyl or cycloheptyl.
In accordance with the present invention, a hydroxamic acid derivative is produced by reacting a carboxylic acid corresponding to the hydroxamic acid with an hydroxylammonium salt of an organic acid. The carboxylic acid corresponding to the hydroxamic acid derivative having the formula R—COOH, wherein R is any organic residue which when taken together with a carboxyl group forms an organic acid, is reacted with a hydroxylammonium salt of an organic acid having the formula NH
2
OH.HA, wherein HA is an organic acid which is preferably different from the carboxylic acid corresponding to the hydroxamic acid derivative, to produce a hydroxamic acid derivative having the formula
Preferably, the R group of the carboxylic acid corresponding to the hydroxamic acid does not contain a reactive group.
In the hydroxylammonium salt of the organic acid, i.e., the hydroxylammonium carboxylate, the anion is derived from an organic carboxylic acid of the general formula R
4
—C(O)OH. R
4
can be any organic residue such as alkyl, cycloalkyl or an aryl and the like which residues (except H) can optionally be further substituted by halogen, nitro, carboxy and the like. Accordingly, dicarboxylic acids like oxalic acid, malonic acid, succinic acid, maleic acid or phthalic acid may be used as well. Monocarboxylic acids are preferred. Preferred carboxylic acid salts are hydroxylammonium acetate, hydroxylammonium propionate, hydroxylammonium benzoate and the like. Such salts have a higher solubility in organic solvents and, therefore, a better reactivity than the inorganic acid salts. Moreover, the carboxylate is a weak base which, based upon its reaction with the free protons in the reaction mixture, provides better reactivity of the non-protonized reagents and causes less side reactions. Most preferably, hydroxylammonium acetate is used.
The hydroxylammonium carboxylates can be prepared by treating a 50% solution of hydroxylamine in water with a carboxylic acid corresponding to the hydroxylamine in an alcohol such as methanol, ethanol or propanol at temperatures from −10 to 30° C. After cooling to temperatures below −10° C. the salt can be crystallized and subsequently washed and dried. Alternatively, DE 3601216 A1 also discloses a process for the preparation of hydroxylammonium salts of fatty acids with 1 to 4 carbon atoms, especially the acetate and the propionate, by reacting hydroxylammonium sulfate and alkali fatty acid salts in a suitable solvent. The preparation of organic acid salts has also been described in U.S. Pat. No. 2,483,252 and in EP 0 108 294 A2 where the oxalate, acetate, benzoate and formate salts are described.
For the introduction of the hydroxylamine group into the carboxylic acid R—COOH the carboxyl group is preferably activated. Any conventional method for activating the carboxyl group can be utilized. For example, this can be effected with activating agents known per se, such as carbodiimides, e.g. dicyclohexylcarbodiimide, or an isocyanide, e.g. tert-butyl isocyanide or, preferably, 2-morpholino-ethyl isocyanide in the presence of stoichiometric amounts of active ester-forming alcohols, such as e.g. N-hydroxy-succinimide, N-hydroxybenzotriazole or preferably N-hydroxy-2-pyridone, in a solvent, such as an ether, e.g. tert-butyl methyl ether, tetrahydrofuran or dioxane, or a hydrocarbon, e.g. toluene, or a halogenated hydrocarbon, e.g. CH
2
Cl
2
, CCl
4
, preferably methylene chloride, or a nitrile, e.g. CH
3
CN, or an ester, e.g. methyl- or ethyl acetate, preferably ethyl acetate, or an alcohol, e.g. methanol or ethanol, at a temperature of 0 to 80°, preferably 10 to 25°.
The temperature and pressure under which the reaction is carried out are not critical. The reaction can be performed at room temperature and atmospheric pressure. The reaction can optionally be performed with the addition of a base in order to neutralize the acid generated from the hydroxylammonium salt. In a preferred emb
Chang Ceila
Hoffmann-La Roche Inc.
Johnston George W.
Tramaloni Dennis P.
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