Phenyl sulfamate derivatives

Details Phenyl sulfamate derivatives Phenyl sulfamate derivatives

2002-01-03

2004-07-13

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C514S601000, C514S608000, C514S520000, C514S524000, C562S037000, C562S045000

Reexamination Certificate

active

06762205

ABSTRACT:

TECHNICAL FIELD
This invention relates to novel phenyl sulfamate derivatives or salts thereof. More particularly, it relates to phenyl sulfamate derivatives represented by the following formula, or salts thereof.
wherein
R
1
and R
2
each independently represent a hydrogen atom or a lower alkyl group;
R
3
represents a hydrogen atom, a halogen atom, a lower alkyl group, —OSO
2
NR
1
R
2
, a lower alkanoylamino group, a nitro group or a cyano group; and
A represents a substituted or unsubstituted phenyl group, a naphthyl group, a pyridyl group, 2-substituted thiazol-4-yl group, 3-substituted isoxazol-5-yl group, 1-cyano-2-(substituted or unsubstituted phenyl)vinyl group, 2-cyano-2-(substituted or unsubstituted phenyl)vinyl group, or a group of the formula—X—NR
4
R
5
[in which X represents CO or CH
2
, R
4
represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted phenyl group, a lower alkanoyl group, a substituted or unsubstituted phenylcarbonyl group, a heteroarylcarbonyl group, a lower alkylsulfonyl group, a sulfamoyl group, a lower alkanoylamino group, a di(lower alkyl)amino group, a heteroaryl group, a heteroaryl-substituted lower alkyl group, or a substituted or unsubstituted phenylmethyl group, and R
5
represents a hydrogen atom, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted phenylcarbonyl group, provided that
{circle around (1)} when X represents CO, R
4
represents a group other than a lower alkanoyl group, a substituted or unsubstituted phenylcarbonyl group, a heteroarylcarbonyl group, a lower alkylsulfonyl group, and a sulfamoyl group, and R
6
represents a group other than a substituted or unsubstituted phenylcarbonyl group;
{circle around (2)} when R
4
represents a lower alkanoyl group, a substituted or unsubstituted phenylcarbonyl group, a heteroarylcarbonyl group, a lower alkylsulfonyl group, or a sulfamoyl group, X represents CH
2
and R
5
represents a group other than a substituted or unsubstituted phenylcarbonyl group; and
{circle around (3)} when R
5
represents a substituted or unsubstituted phenylcarbonyl group, X represents CH
2
and R
4
represents a group other than a lower alkanoyl group, a substituted or unsubstituted phenylcarbonyl group, a heteroarylcarbonyl group, a lower alkylsulfonyl group, and a sulfamoyl group]; or
R
3
and A, together with the phenyl group to which they are attached, represent a fluoren-2-yl or 9-oxofluoren-2-yl group; provided that, when R
3
represents a hydrogen atom, A does not represent an unsubstituted phenyl group.
BACKGROUND ART
Steroid sulfates such as dehydroepiandrosterone sulfate, cholesterol sulfate and estrone sulfate are intermediate products in the steroid metabolism within the human body. For example, estrone sulfate is hydrolyzed by steroid sulfatase present in the living body to yield estrone in free form. It is also known that, in the living body, this estrone is further converted reversibly into estradiol by the action of 17&bgr;-hydroxysteroid dehydrogenase. These estrogens formed in the steroid metabolism, such as estrone and estradiol are considered to be closely associated with diseases such as breast cancer, uterine cancer, ovarian cancer, endometriosis, adenomyosis uteri and mastopathy.
Accordingly, it is believed that, if the action of steroid sulfatase can be effectively inhibited, this would be effective for the treatment of diseases associated with steroids such as estrogens. From this point of view, several steroidal compounds having an inhibitory effect on steroid sulfatase, as typified by estrone 3-sulfamate (EMATE), have been proposed (see Published Japanese Translation of PCT International Publication No. 501515/'95).
However, although EMATE has a powerful inhibitory effect on steroid sulfatase, it also has a powerful estrogenic action and is hence a compound which is unsuitable for use as a drug for the treatment of diseases associated with estrogens.
Moreover, as nonsteroidal compounds having an inhibitory effect on steroid sulfatase, certain coumarin derivatives [e.g., 4-methylcoumarin 7-sulfamate (COUMATE)] have been proposed [see J. Med. Chem., Vol. 37, 219(1994)]. Furthermore, certain phenyl sulfamate derivatives [e.g., 4-(2-myristoylaminoethyl)phenyl sulfamate (DU-14)]have also been proposed [see J. Med. Chem., Vol. 39, 1349(1996)]. In addition, steroid sulfatase inhibitors having a specific ring system and a sulfamoyloxy group are also known (see U.S. Pat. No. 6,011,024 and the pamphlet of International Publication of PCT Application No. WO2000/18397).
These nonsteroidal compounds such as COUMATE and DU-14 do not show an estrogenic action as a side effect. However, their principal action (i.e., their inhibitory effect on steroid sulfatase) is weak and, therefore, these compounds are not satisfactory as yet.
Japanese Patent Laid-Open No. 47162/'91 and U.S. Pat. No. 5,192,785 disclose certain sulfamate compounds. Although it is described therein that those compounds are useful as drugs for the treatment of chronic arthritis, osteoporosis, glaucoma and the like, neither mention nor suggestion is made of their inhibitory effect on steroid sulfatase.
The present inventors have now found that novel phenyl sulfamate derivatives in which the phenyl group is substituted by a specific substituent (e.g., substituted or unsubstituted phenyl, N-substituted aminomethyl or N-substituted carbamoyl), or salts thereof exhibit a powerful inhibitory effect on steroid sulfatase without showing an estrogenic action as a side effect.
Thus, the present invention provides phenyl sulfamate derivatives represented by the above formula (I), or salts thereof.
DISCLOSURE OF THE INVENTION
The term “lower” as used herein means that the group or compound modified by this term has 6 or less carbon atoms and preferably 4 or less carbon atoms.
Thus, examples of the “lower alkyl group” include methyl ethyl n-propyl isopropyl n-butyl isobutyl sec-butyl, tert-butyl and n-hexyl, and examples of the “lower alkoxy group” include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and n-hexyloxy. Moreover, examples of the “lower alkylenedioxy group” include methylenedioxy, ethylenedioxy and trimethylenedioxy, and examples of the “lower alkanoyl group” include acetyl propionyl butyryl isobutyryl and pentanoyl.
The “lower alkanoylamino group” is an amino group substituted by the above-defined “lower alkanoyl group”, and examples thereof include acetylamino, propionylamino and butyrylamino. The “di(lower alkyl)amino group” is an amino group di-substituted by the above-defined “lower alkyl group”, and examples thereof include dimethylamino, diethylamino and dipropylamino. The “lower alkylsulfonyl group” is a sulfonyl group substituted by the above-defined “lower alkyl group”, and examples thereof include methanesulfonyl and ethanesulfonyl.
“—OSO
2
NR
1
R
2
” is a sulfamoyloxy group whose N atom may optionally be mono- or di-substituted by the above-defined “lower alkyl group”. Examples thereof include, besides unsubstituted sulfamoyloxy, N-methylsulfamoyloxy, N,N-dimethylsulfamoyloxy and N,N-diethylsulfamoyloxy.
“—NHSO
2
NR
1
R
2
” is a sulfamoylamino group whose N atom may optionally be mono- or di-substituted by the above-defined “lower alyl group”. Examples thereof include, besides unsubstituted sulfamoylamino, N-methylsulfamoylamino, N,N-dimethylsulfamoylamino and N,N-diethylsulfamoylamino.
The “organic sulfonyloxy group” is a hydroxyl group substituted by an “organic sulfonyl group” which is a residue obtained by eliminating a hydroxyl group (OH) from an organic sulfonic acid, and preferred examples thereof include methanesulfonyloxy, p-toluenesulfonyloxy and benzenesulfonyloxy. The “organic sulfonylamino group” is an amino group substituted by the above-defined “organic sulfonyl group”, and preferred examples thereof include methanesulfonylamino, p-toluenesulfonylamino and benzenesulfonylamino.
The “aralkyl group” is an alkyl group substituted by a monocyclic or polycyclic aryl group such as phenyl

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