Phenyl sulfamate derivatives Number:6,762,205 from the United States Patent and Trademark Office (PTO) owispatent Phenyl sulfamate derivatives represented by the following formula or salts thereof have a powerful inhibitory effect on steroid sulfatase and are hence useful for the prophylaxis or treatment of diseases associated with steroids such as estrogens, such as breast cancer, corpus uteri cancer, endometrial hyperplasia, infertility, endometriosis, adenomyosis uteri, autoimmune disease, dementia or Alzheimer's disease. ##STR1##wherein R.sup.1 and R.sup.2 each independently represent a hydrogen atom or a lower alkyl group; R.sup.3 represents a hydrogen atom, a halogen atom, a lower alkyl group, --OSO.sub.2 NR.sup.1 R.sup.2, a lower alkanoylamino group, a nitro group or a cyano group; and A represents a substituted or unsubstituted phenyl group, a group of the formula --X--NR.sup.4 R.sup.5, or the like.<H derivatives, sulfamate, Phenyl, sulfamat, 6762205.html, Patent, pto, 6762205

Title: Phenyl sulfamate derivatives

Abstract: Phenyl sulfamate derivatives represented by the following formula or salts thereof have a powerful inhibitory effect on steroid sulfatase and are hence useful for the prophylaxis or treatment of diseases associated with steroids such as estrogens, such as breast cancer, corpus uteri cancer, endometrial hyperplasia, infertility, endometriosis, adenomyosis uteri, autoimmune disease, dementia or Alzheimer's disease. ##STR1##wherein R.sup.1 and R.sup.2 each independently represent a hydrogen atom or a lower alkyl group; R.sup.3 represents a hydrogen atom, a halogen atom, a lower alkyl group, --OSO.sub.2 NR.sup.1 R.sup.2, a lower alkanoylamino group, a nitro group or a cyano group; and A represents a substituted or unsubstituted phenyl group, a group of the formula --X--NR.sup.4 R.sup.5, or the like.

Patent Number: 6,762,205 Issued on 07/13/2004 to Koizumi, et al.

Inventors: Koizumi; Naoyuki (Sagamihara, JP), Okada; Makoto (Inagi, JP), Iwashita; Shigeki (Kawasaki, JP), Takegawa; Shigehiro (Kawasaki, JP), Nakagawa; Takayoshi (Fujisawa, JP), Takahashi; Hiroo (Sagamihara, JP), Fujii; Tomohito (Kawasaki, JP)
Assignee: Teikoku Hormone Mfg. Co., Ltd. (Tokyo, JP)

Appl. No.: 10/019,693

Filed: January 3, 2002

PCT Filed: July 04, 2000

PCT No.: PCT/JP00/04427

PCT Pub. No.: WO01/02349

PCT Pub. Date: January 11, 2001

Foreign Application Priority Data


Jul 06, 1999 [JP]			11/191632

Current U.S. Class: 514/602 ; 514/520; 514/524; 514/601; 514/608; 562/37; 562/45

Current International Class: C07C 307/02 (20060101); C07C 307/00 (20060101); C07D 239/42 (20060101); C07D 239/00 (20060101); C07D 241/00 (20060101); C07D 241/20 (20060101); C07D 213/00 (20060101); C07D 521/00 (20060101); C07D 213/30 (20060101); C07D 213/82 (20060101); C07D 277/00 (20060101); C07D 213/74 (20060101); C07D 277/24 (20060101); C07D 333/00 (20060101); C07D 333/20 (20060101); C07D 333/38 (20060101)

Field of Search: 514/601,602,608,518,520,524 562/37,45

References Cited [Referenced By]

U.S. Patent Documents


3082238	March 1963	Dunbar et al.
5025031	June 1991	Lo et al.
5192785	March 1993	Lo et al.

Foreign Patent Documents


403185	Dec., 1990	EP
1136687	Sep., 1962	JP
56-83467	Jul., 1981	JP
56083467	Jul., 1981	JP
97/32872	Sep., 1997	WO

Other References

Chemical Abstract DN 59:21587, also cited as DE 1136687.* .
Chemical Abstract DN 59:21586, also cited as U.S.P. 3082238.* .
Chemical Abstract DN 95:186905, also cited as JP 56083467.* .
Chemical abstract DN 119:249709, also cited as USP5192785.* .
Chemica Abstract DN115:255820, also cited as 5025031.* .
Chemical Abstract DN 116:20788, also cited as EP 403185.* .
A. Purohit et al., "Recent Advances in the Development of Steroid Sulfatase Inhibitors", J. Steroid Biochem. Mol. Biol., 1999, vol. 69, No. 1-6, pp. 227-238. .
Aparna Kolli et al., "Development of(p-O-sulfamoyl)-N-alkanoyl-phenylalkyl amines as non-steroidal estrone sulfatase inhibitors", J. Steroid Biochem. Mol. Biol., 1999, vol. 68, No. 1-2, pp. 31-40. .
Guo-Hua Chu et al., "Synthesis and sulfatase inhibitory activities of (E)- and (Z) -4-hydroxytamoxifen sulfamates", Bioorg. Med. Chem. Lett., 1999, vol. 9, No. 2, pp. 141-144..

Primary Examiner: Raymond; Richard L.
Assistant Examiner: Patel; Sudhaker B.
Attorney, Agent or Firm: Wenderoth, Lind & Ponack, LLP

Claims

What is claimed is:

1. A compound of Formula [I] or its pharmaceutically acceptable salts: ##STR9##

wherein: R.sup.1 and R.sup.2 each independently represent a hydrogen atom; R.sup.3 represents a hydrogen atom, a halogen atom, a lower alkyl group, --OSO.sub.2 NR.sup.1 R.sup.2, a lower alkanoylamino group, a nitro group or a cyano group; and A represents a group represented by the following formula: ##STR10## where X.sup.1 and X.sup.2 each independently represent a hydrogen atom, a halogen atom, a halogen-substituted lower alkyl group, a cyano-substituted lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group, an organic sulfonyloxy group, an amino group, a lower alkanoylamino group, --NHSO.sub.2 NR.sup.1 R.sup.2, an organic sulfonylamino group, a nitro group, a cyano group, a carboxyl group or a lower alkoxycarbonyl group, or a naphthyl group; provided that, when R.sup.3 represents a hydrogen atom, either X.sup.1 or X.sup.2 represents a group which is not a hydrogen atom.

2. A compound of Formula [I] or its pharmaceutically acceptable salts as claimed in claim 1 wherein R.sup.3 represents a hydrogen atom or a halogen atom.

3. A compound of Formula [I] or its pharmaceutically acceptable salts as claimed in claim 1 wherein A is located at the 4-position.

4. A compound of Formula [I] or its pharmaceutically acceptable salts as claimed in claim 1 wherein A represents a group represented by the following formula: ##STR11##

where X.sup.1 and X.sup.2 each independently represent a hydrogen atom, a halogen atom, a halogen-substituted lower alkyl group, a cyano-substituted lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group, an organic sulfonyloxy group, an amino group, a lower alkanoylamino group, --NHSO.sub.2 NR.sup.1 R.sup.2, an organic sulfonylamino group, a nitro group, a cyano group, a carboxyl group or a lower alkoxycarbonyl group.

5. A compound of Formula [I] or its pharmaceutically acceptable salts as claimed in claim 3 wherein X.sup.1 and X.sup.2 are each located at the 2- or 4-position of the phenyl group.

6. A steroid sulfatase inhibitor containing a steroid sulfatase-inhibiting amount of a compound of Formula [I] or its pharmaceutically acceptable salt as claimed in claim 1.

7. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula [I] or its pharmaceutically acceptable salt as claimed in claim 1, and a pharmaceutically acceptable adjuvant.

8. A method for the treatment of breast cancer, which comprises administering a pharmaceutically effective amount of a compound of Formula [I] or it pharmaceutically acceptable salt as claimed in claim 1, to a human being in need thereof.

Description

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. ##STR2##

wherein R.sup.1 and R.sup.2 each independently represent a hydrogen atom or a lower alkyl group; R.sup.3 represents a hydrogen atom, a halogen atom, a lower alkyl group, --OSO.sub.2 NR.sup.1 R.sup.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.sup.4 R.sup.5 [in which X represents CO or CH.sub.2, R.sup.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.sup.5 represents a hydrogen atom, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted phenylcarbonyl group, provided that 1 when X represents CO, R.sup.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.sup.6 represents a group other than a substituted or unsubstituted phenylcarbonyl group; 2 when R.sup.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.sub.2 and R.sup.5 represents a group other than a substituted or unsubstituted phenylcarbonyl group; and 3 when R.sup.5 represents a substituted or unsubstituted phenylcarbonyl group, X represents CH.sub.2 and R.sup.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.sup.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.sup.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.beta.-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.sub.2 NR.sup.1 R.sup.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.sub.2 NR.sup.1 R.sup.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 or naphthyl, and preferably an aryl-substituted lower alkyl group. Examples thereof include benzyl, 1-phenylethyl, 2-phenylethyl and 1-phenylpropyl.

In the "substituted or unsubstituted phenyl group" used in the definition of A, R.sup.4 and R.sup.5, examples of the substituent(s) on the phenyl group include halogen, lower alkyl, halogen-substituted lower alkyl cyano-substituted lower alkyl, hydroxyl, lower alkoxy, lower alkylenedioxy, lower alkanoyloxy, sulfamoyloxy, N-(lower alkyl)sulfamoyloxy, N,N-di(lower allyl)sulfamoyloxy, organic sulfonyloxy, amino, lower alkylamino, di(lower alkyl)amino, lower alkanoylamino, sulfamoyloxy, N-(lower alkyl)sulfamoyloxy, N,N-di(lower alkyl)sulfamoyl-oxy, organic sulfonylamino, aralkyloxycarbonylamino, lower alkoxycarbonylamino, mercapto, lower alkylthio, lower alkanoylthio, nitro, cyano, carboxyl and lower alkoxycarbonyl, and the phenyl group may be substituted by one to three substituents selected from the foregoing groups. Especially preferred examples of the substituted phenyl group are phenyl groups substituted by one or two substituents selected from halogen, lower alkyl, halogen-substituted lower alkyl cyano-substituted lower alkyl lower alkoxy, lower alkanoyloxy, --OSO.sub.2 NR.sup.1 R.sup.2, organic sulfonyloxy, amino, lower alkanoylamino, --NHSO.sub.2 NR.sup.1 R.sup.2, organic sulfonylamino, nitro, cyano, carboxyl and lower alkoxycarbonyl.

Moreover, in the "substituted or unsubstituted phenylcarbonyl group" used in the definition of R.sup.4 and R.sup.5, examples of the substituent(s) on the phenyl group include the same groups as described above for the "substituted or unsubstituted phenyl group", and the phenyl group may be substituted by one to three substituents selected from them. Especially preferred examples of the substituted phenylcarbonyl group are phenylcarbonyl groups whose phenyl group is substituted by one or two substituents selected from halogen, lower alkyl, lower alkoxy, sulfamoyloxy, nitro and cyano.

Furthermore, in the "substituted or unsubstituted phenylmethyl group" used in the definition of R.sup.4, examples of the substituent(s) on the phenyl group include the same groups as described above for the "substituted or unsubstituted phenyl group", and the phenyl group may be substituted by one to three substituents selected from them. Especially preferred examples of the substituted phenylmethyl group are phenylmethyl groups whose phenyl group is substituted by one or two substituents selected from halogen, lower alkyl, lower alkoxy, sulfamoyloxy, nitro and cyano.

In the "2-substituted thiazol-4-yl or 3-substituted isoxazol-5-yl" used in the definition of A, examples of the substituent include lower alkyl, nitro and cyano.

In the "heteroarylcarbonyl group", "heteroaryl group" and "heteroaryl-substituted lower alkyl group" used in the definition of R.sup.4, the term "heteroaryl" means a monocyclic or polycyclic unsaturated heterocyclic group which contains 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms and which includes a five- to seven-membered ring. Alternatively, the heterocyclic ring may further be fused with an aromatic hydrocarbon ring to form a fused ring. Among such heteroaryl groups, preferred ones are five- or six-membered monocyclic heterocyclic groups containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms.

Thus, examples of such "heteroaryl groups" include pyrrolyl, furyl, thienyl, imidazolyl, pirazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyranyl, pyrimidinyl, pyridazinyl, pyrazinyl, azepinyl, purinyl, naphthyridinyl, pteridinyl, benzothienyl, benzofuranyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, chromenyl, phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenanthridinyl, acridinyl and dibenzazepinyl.

When A represents a group of the formula --X--NR.sup.4 R.sup.5, and X, R.sup.4 and/or R.sup.5 have a --CO-- or --SO.sub.2 -- moiety attached directly to the N atom in this formula, this group should not contain more than one such moiety. Accordingly, in the group of the formula --X--NR.sup.4 R.sup.5, 1 when X represents CO, R.sup.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.sup.5 represents a group other than a substituted or unsubstituted phenylcarbonyl group; 2 when R.sup.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.sub.2 and R.sup.5 represents a group other than a substituted or unsubstituted phenylcarbonyl group; and 3 when R.sup.5 represents a substituted or unsubstituted phenylcarbonyl group, X represents CH.sub.2 and R.sup.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.

Moreover, the term "halogen atom" comprehends fluorine, chlorine, bromine and iodine atoms.

One preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which both R.sup.1 and R.sup.2 represent hydrogen atoms.

Another preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which R.sup.3 represents a hydrogen atom or a halogen atom.

Still another preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which A is located at the 4-position.

A further preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which A represents a substituted phenyl group or a group of the formula --X--NR.sup.4 R.sup.5.

Still a further preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which the substituted phenyl group defined for A is a phenyl group substituted by one or two substituents selected from halogen, lower alkyl halogen-substituted lower alkyl, cyano-substituted lower alkyl, lower alkoxy, lower alkanoyloxy, --OSO.sub.2 NR.sup.1 R.sup.2, organic sulfonyloxy, amino, lower alkanoylamino, --OSO.sub.2 NR.sup.1 R.sup.2, organic sulfonylamino, nitro, cyano, carboxyl and lower alkoxycarbonyl.

Still a further preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which, in the substituted phenyl group defined for A, the substituent or substituents are located at the 2- and/or 4-positions of the phenyl group.

Still a further preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which A represents a group of the formula --X--NR.sup.4 R.sup.5 and R.sup.4 represents a hydrogen atom, a lower alkyl group or a heteroaryl group.

Still a further preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which the heteroaryl group defined for R.sup.4 is a five- or six-membered monocyclic heteroaryl group containing 1 to 3 nitrogen atoms.

Still a further preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which R.sup.5 represents a substituted phenyl group, such as a phenyl group substituted by one or two substituents selected from hydroxyl, lower alkanoyloxy, --OSO.sub.2 NR.sup.1 R.sup.2, nitro and cyano.

In addition to the compounds described in the examples which will be given later, typical examples of the compounds of the above formula (I) which are provided by the present invention include: 2'-nitrobiphenyl-4-yl N-methylsulfamate, 2'-cyanobiphenyl-4-yl N,N-dimethylsulfamate, 4'-nitrobiphenyl-4-yl N,N-dimethylsulfamate, 4-[N-(4-cyanophenyl)-N-(1,2,4-triazol-4-yl)aminomethyl]phenyl N,N'-dimethylsulfamate, 2'-bromobiphenyl-4-yl sulfamate, 4'-methylbiphenyl-4-yl sulfamate, 4'-hydroxybiphenyl-4-yl sulfamate, 3',4'-methylenedioxybiphenyl-4-yl sulfamate, 4'-sulfamoyloxybiphenyl-4-yl acetate, biphenyl-4,4'-diyl 4-(N,N-dimethylsulfamate) 4'-sulfamate, 4'-aminobiphenyl-4-yl sulfamate, 4'-acetylaminobiphenyl-4-yl sulfamate, 4'-dimethylaminobiphenyl-4-yl sulfamate, 4'-sulfamoyloxybiphenyl-4-carboxylic acid, 4'-methylthiobiphenyl-4-yl sulfamate, 2'-cyanobiphenyl-4,4'-diyl disulfamate, 2'-cyano-4'-trifluoromethylbiphenyl-4-yl sulfamate, methyl 2'-cyano-4'-sulfamoyloxy-4-biphenylcarboxylate, 2'-cyano-4'-cyanomethylbiphenyl-4-yl sulfamate, 4-cyanobiphenyl-2,4'-diyl disulfamate, biphenyl-2,4,4'-triyl trisulfamate, 3-chloro-2'-cyanobiphenyl-4-yl sulfamate, 3-chloro-4'-nitrobiphenyl-4-yl sulfamate, 3-chlorobiphenyl-4,4'-diyl disulfamate, 3-chloro-2'-cyano-4'-nitrobiphenyl-4-yl sulfamate, 2-methyl-2'-nitrobiphenyl-4-yl sulfamate, 2'-cyano-2,4'-dinitrobiphenyl-4-yl sulfamate, 2-nitrobiphenyl-4,4yl-4,4'-diyl disulfamate, 2,4'-dicyanobiphenyl-4-yl sulfamate, 4-(2-pyridyl)phenyl sulfamate, 4-(2-cyanothiazol-4-yl)phenyl sulfamate, 4-(3-methylisoxazol-5-yl)phenyl sulfamate, 4-[N-(4-sulfamoyloxyphenyl)aminomethyl]phenyl sulfamate, methyl 4-[N-(4-sulfamoyloxybenzoyl)amino]benzoate, 4-[N-(4-bromophenyl)carbamoyl]phenyl sulfamate, 4-[N-(4-trifluoromethylphenyl)carbamoyl]phenyl sulfamate, 4-[N-(4-nitrophenyl)carbamoyl]phenyl sulfamate, 4-[N-(4-cyanomethylphenyl)carbamoyl]phenyl sulfamate, 4-[N-(2-cyano-4-nitrophenyl)carbamoyl]phenyl sulfamate, 4-[N-ethyl-N-(4-sulfamoyloxyphenyl)aminomethyl]phenyl sulfamate, 4-[N-(4-cyanophenyl)-N-(4-sulfamoyloxyphenyl)carbamoyl]phenyl sulfamate, 4-[N,N-di(4-sulfamoyloxyphenyl)carbamoyl]phenyl sulfamate, 4-[N-(4-acetyl-N-(4-cyanophenyl)aminomethyl]phenyl sulfamate, 4-[N-benzoyl-N-(4-sulfamoyloxybenzyl)amino]phenyl sulfamate, 4-(sulfamoylaminomethyl)phenyl sulfamate, 4-[N'-acetyl-N-(4-sulfamoyloxyphenyl)hydrazinocarbonyl]phenyl sulfamate, 4-(N',N'-dimethyl-N-phenylhydrazinocarbonyl)phenyl sulfamate, 4-[N-(4-sulfamoyloxyphenyl)-N-(1,2,4-triazol-4-yl)carbamoyl]-phenyl sulfamate, 4-[N-(2-nitrophenyl)-N-(1,2,4-triazol-4-yl)carbamoyl]phenyl sulfamate, 4-[N-(4-nitrophenyl)-N-(1,2,4-triazol-4-yl)aminomethyl]phenyl sulfamate, 4-[N-(2-cyanophenyl)-N-(1,2,4-triazol-4-yl)aminomethyl]phenyl sulfamate, 4-[N-(4-cyanophenyl)-N-(pyrazol-1-yl)aminomethyl]phenyl sulfamate, 4-[N-(4-cyanophenyl)-N-(imidazol-1-yl)aminomethyl]phenyl sulfamate, 4-[N-(4-cyanophenyl)-N-(tetrazol-1-yl)aminomethyl]phenyl sulfamate, 4-[N-benzoyl-N-ethylaminomethyl]phenyl sulfamate, 2-chloro-4-[N-(4-cyanophenyl)-N-(1,2,4-triazol-4-yl)aminomethyl]phenyl sulfamate, 4-[N-(4-cyanophenyl)-N-(1,2,4-triazol-4-yl)aminomethyl]-3-nitrophenyl sulfamate, 2'-cyanobiphenyl-3-yl sulfamate biphenyl-3,4'-diyl disulfamate, and 2'-cyano-4'-nitrobiphenyl-3-yl sulfamate.

Depending on the type of substituent A, the compounds of formula (I) in accordance with the present invention may optionally form salts. Examples of such salts include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; salts formed with organic acids such as acetic acid, oxalic acid, citric acid, lactic acid, tartaric acid and p-toluenesulfonic acid; alkali metal salts such as sodium, potassium and lithium salts; alkaline earth metal salts such as calcium and magnesium salts; salts formed with organic bases such as triethylamine, dicyclohexylamine, pyrrolidine, morpholine and pyridine; and ammonium salts. Among others, pharmaceutically acceptable salts are preferred.

According to the present invention, the compounds of the above formula (I) may be prepared, for example, by reacting an phenol derivative of the formula ##STR3##

wherein A and R.sup.3 have the above-defined meanings, with an amidosulfonic acid chloride of the formula ##STR4##

wherein R.sup.1 and R.sup.2 have the above-defined meanings.

This reaction may generally be carried out in an inert solvent selected, for example, from amides such as N,N-dimethylformamide and N-methylpyrrolidone; alkyl halides such as dichloromethane and dichloroethane; and organic bases such as pyridine, optionally in the presence of an alkali such as sodium hydride, sodium methoxide, potassium butoxide, potassium hydroxide or potassium phosphate, or an organic base such as triethylamine or 2,6-di-tert-butyl-4-methylpyridine, at a temperature ranging from about -20.degree. C. to the reflex temperature of the reaction mixture and preferably from about 0.degree. C. to room temperature.

No particular limitation is placed on the proportion of the amidosulfonic acid chloride of formula (III) to the compound of formula (II). However, the amidosulfonic acid chloride may generally be used in an amount of at least 1 mole, preferably about 1.1 to 20 moles, and more preferably about 2 to 10 moles, per mole of the compound of formula (II). Moreover, the aforesaid alkali is suitably used in an amount of about 2 to about 10 moles per mole of the compound of formula (II).

The compounds of the above formula (I) in which both R.sup.1 and R.sup.2 represent hydrogen atoms may also be prepared by reacting a phenol derivative of the above formula (II) with chlorosulfonyl isocyanate and then treating the resulting product with water.

The aforesaid reaction of the phenol derivative of formula (II) with chlorosulfonyl isocyanate may generally be carried out in an inert solvent selected, for example, from aromatic hydrocarbons such as toluene and xylene; halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene; and acetonitrile, at a temperature ranging from 50.degree. C. to the reflex temperature of the reaction mixture and preferably from 80.degree. C. to the reflex temperature of the reaction mixture.

No particular limitation is placed on the proportion of chlorosulfonyl isocyanate to the phenol derivative of formula (II). However, chlorosulfonyl isocyanate may generally be used in an amount of at least 1 mole and preferably about 1.01 to 2 moles, per mole of the compound of formula (II).

The subsequent treatment with water may usually be carried out simply by adding water to the reaction mixture resulting from the aforesaid reaction.

The compounds of the above formula (I) in which X represents CH.sub.2, R.sup.5 represents a hydrogen atom, and R.sup.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 may also be prepared, for example, by reacting an aldehyde compound of the formula ##STR5##

wherein R.sup.1, R.sup.2 and R.sup.3 have the above-defined meanings, with an amino compound of the formula

wherein R.sup.41 represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted phenyl 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 reducing the Schiff base so formed.

The aforesaid reaction of the aldehyde compound of formula (IV) with the amino compound of formula (V) may generally be carried out in the absence of solvent, or in a solvent selected from water; alcohols such as methanol and ethanol; ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane and dioxane; alkanoic acids such as acetic acid and propionic acid; and amides such as dimethylformamide and dimethylacetamide, at a temperature ranging from 0.degree. C. to the reflex temperature of the reaction mixture and preferably from room temperature to 100.degree. C.

No particular limitation is placed on the proportion of the amino compound of formula (V) to the aldehyde compound of formula (IV). However, the amino compound of formula (V) may generally be used in an amount of at least 1 mole, preferably about 1.1 to 20 moles, and more preferably about 2 to 10 moles, per mole of the compound of formula (IV).

The reduction of the Schiff base may usually be carried out simply by adding a complex metal hydride (e.g., sodium borohydride or sodium cyanoborohydride) to the reaction mixture containing the Schiff base formed and reacting this mixture at a reaction temperature ranging from about 0.degree. C. to room temperature.

Thus, the compounds of the above formula (I) which are desired in the present invention can be formed.

Among the compounds of the above formula (II) which are used as starting materials in the aforesaid reactions, most of the compounds in which A represents a substituted or unsubstituted phenyl group, a naphthyl group, a pyridyl group, a 4-substituted thiazol-2-yl group, a 3-substituted isoxazol-5-yl group, a 1-cyano-2-(substituted or unsubstituted phenyl)vinyl group, or a 2-cyano-2-(substituted or unsubstituted phenyl)vinyl group are known compounds described in the literature of the prior art. In the case of novel compounds, they may be easily prepared in the same manner as the known compounds. For example, the compounds of formula (II) in which A represents a substituted phenyl group may be prepared by reacting a substituted phenyl halide compound with a 4-methoxyphenylboric acid compound and eliminating the hydroxyl-protecting group of the resulting substituted anisole compound with the aid of a Lewis acid (e.g., boron tribromide or aluminum chloride) or an acid (e.g., hydrobromic acid). For details on the reaction conditions and the like, refer to Preparation Examples 1 and 2 which will be given later.

On the other hand, most of the compounds of the above formula (II) in which A represents --X--NR.sup.4 R.sup.5 are novel compound which have not been described in the literature of the prior art. Depending on the type of the substituent R.sup.5, they may be prepared, for example, by following the pathway shown in Reaction Scheme 1 or 2 given below. For details on the reaction conditions and the like, refer to Preparation Examples 7-11, 14, 20, 22, 23, 25, 28, 29, 31, 34, 35, 38, 47 and 52 which will be given later.

When R.sup.5 represents a hydrogen atom or a substituted or unsubstituted phenyl group: ##STR6##

In the above formulas, Y represents a hydroxyl-protecting group; and X, R.sup.3, R.sup.4 and R.sup.5 have the above-defined meanings.

When R.sup.5 represents a substituted or unsubstituted phenylcarbonyl group: ##STR7##

In the above formulas, Y, R.sup.3, R.sup.4 and R.sup.5 have the above-defined meanings.

Moreover, most of the aldehyde compounds of the above formula (IV) which are used as starting materials in the aforesaid reaction are novel compounds which have not been described in the literature of the prior art. They may be easily prepared, for example, by reacting an aldehyde compound of the formula ##STR8##

wherein R.sup.3 has the above-defined meaning, with an amidosulfonic acid chloride of the above formula (III) in the same manner as described in connection with the reaction of a compound of the above formula (II) with an amidosulfonic acid chloride of the above formula (III). For details on the reaction conditions of this reaction, and the like, refer to Preparation Example 24 which will be given later.

When the compounds used in each of the aforesaid reactions contain substituents (e.g., hydroxyl, amino and carboxyl) which may participate in the reaction, these substituents may be protected by protecting groups as required. These protected by protecting groups may be eliminated after completion of the reaction.

Thus, the compounds of the above formula (I) which are formed according to the processes of the present invention may be isolated and purified from the reaction mixture by per se known techniques such as recrystallization, distillation, column chromatography and thin-layer chromatography.

The above-described phenyl sulfamate derivatives of formula (I) or salts thereof in accordance with the present invention have a powerful inhibitory effect on steroid sulfatase and are hence effective for the treatment of diseases associated with steroids (e.g., estrogens), such as breast cancer, corpus uteri cancer, ovarian cancer, endometrial hyperplasia, infertility, endometriosis, adenomyosis uteri, hysteromyoma, autoimmune diseases, dementia, Alzheimer's disease, mastopathy, gynecomastia in the male, prostatomegaly, and male infertility due to oligospermia.

The inhibitory effect on steroid sulfatase of compounds of formula (I) in accordance with the present invention can be measured according to the following procedure.

(1) Measurement of an In vitro Inhibitory Effect on Steroid Sulfatase

Six-well plates (9.4 cm.sup.2 /well) were inoculated with intact MCF-7 human breast cancer cells at a density of about 1.times.10.sup.5 cells/well. Using Dulbecco's modified Eagle medium (DMEM) containing 10 mM HEPES, 5% fetal bovine serum, 0.011% sodium pyruvate and 0.37% sodium bicarbonate, the cells were grown to 80% confluency.

The plates were washed with Earle's balanced salt solution (EBSS from Life Technologies Inc., Grand Island, N.Y., USA). Then, serum-free DMEM (2 ml) containing 4 pmol (4.4.times.10.sup.5 dpm) of [6,7-.sup.3 H]estrone 3-sulfate (with a specific activity of 49 Ci/mmol; from New England Nuclear, Boston, Mass., USA), together with a test compound, was placed on each plate and incubated at 37.degree. C. for 20 hours. After incubation, the plate was cooled, and the medium (1 ml) was pipetted into a separating tube containing [4-.sup.14 C]estrone (6.times.10.sup.3 dpm) (with a specific activity of 52.5 mCi/mmol; from New England Nuclear, Boston, Mass., USA). This mixture, together with toluene (4 ml), was vigorously shaken for 30 seconds. It was shown by experiment that more than 90% of [4-.sup.14 C]estrone was removed from the aqueous layer by this treatment. A portion (2 ml) of the organic phase was taken, and the .sup.3 H and .sup.14 C contents thereof were measured by scintillation spectrometry. Then, the amount of estrone 3-sulfate hydrolyzed was calculated from the total 3H count (corrected for the volumes of the medium used and the organic phase, and for the recovery of the [.sup.14 C]estrone added) and the specific activity of the substrate. The results thus obtained are shown in the following Table 1.

TABLE 1 Example No. Inhibitory rate of compound (3 .times. 10.sup.-9 M. %) Example 3 76 Example 23 67 Example 25 87 Example 27 94

(2) Measurement of an In vivo Inhibitory Effect on Steroid Sulfatase

A test compound was suspended in a 0.5% polyoxyethylene (20) sorbitan monooleate solution (Tween 80) and administered, once a day, to a group of 5 female SD strain rats (weighing 168-194 g) for 5 days.

Four hours after the final administration, all rats were sacrificed by ether anesthesia and dissected. Thus, the liver and the uterus were excised from each rat, washed once with cold phosphate-buffered saline (PBS, pH 7.4), and preserved at -70.degree. C. or below. Each of the liver and the uterus was finely minced with scissors, and suspended in PBS containing 250 mM sucrose (5 ml/g tissue). Under cooling with ice, each suspension was homogenized with an Ultra-Turrax homogenizer. The resulting homogenate was centrifuged (at 4.degree. C.) at 2,000.times.g for 30 minutes to remove nuclei and cell debris, and the protein concentration in this supernatant was measured according to the method of Bradford [Anal. Biochem. 72, 248-254(1976)].

The homogenate in an amount corresponding to a protein concentration of 100-500 .mu.g/ml was mixed with [6,7-.sup.3 H]estrone 3-sulfate (with a specific activity of 49 Ci/mmol; from New England Nuclear, Boston, Mass., USA) in an amount corresponding to a substrate concentration of 20 .mu.M. This mixture was diluted with PBS to a total volume of 1 ml, and incubated at 37.degree. C. for 30 minutes. After incubation (1 ml), the steroid sulfatase activity was determined in the same manner as described above for the in vitro measurement (1). The results thus obtained are shown in the following Table 2.

TABLE 2 Inhibitory rate Example No. (0.5 mg/kg, p.o., %) of compound Liver Uterus Example 1 91.2 94.9 Example 3 95.4 93.8 Example 16 97.0 100 Example 21 97.2 97.6 Example 25 99.5 100 Example 38 85.3 79.0

Thus, the compounds of formula (I) or salts thereof in accordance with the present invention are useful as steroid sulfatase inhibitors and can hence be used for therapeutic purposes in human beings and other mammals by oral or parenteral administration (e.g., intramuscular injection, intravenous injection, intrarectal administration or percutaneous administration).

When the compounds of the present invention are used as drugs, they may be made into in any of various pharmaceutical preparations (or pharmaceutical compositions) according to the intended purpose. These pharmaceutical preparations include solid preparations (e.g., tablets, hard capsules, soft capsules, granules, powders, fine subtilaes, pills and troches), semisolid preparations (e.g., suppositories and ointments), and liquid preparations (e.g., injections, emulsions, suspensions, lotions and sprays). Pharmaceutically acceptable adjuvants which can be used in the aforesaid pharmaceutical preparations include, for example, starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or salts thereof, acacia, polyethylene glycol, alkyl esters of p-hydroxybenzoic acid, syrup, ethanol propylene glycol petrolatum, carbowax, glycerin, sodium chloride, sodium sulfite, sodium phosphate and citric acid. The aforesaid pharmaceutical preparations may also contain other therapeutically useful drugs.

The content of the compounds of the present invention in the aforesaid pharmaceutical preparations may vary according to the dosage form. Generally, it is desirable that solid and semisolid preparations contain the compounds of the present invention at a concentration of 0.1 to 50% by weight and liquid preparations contain them at a concentration of 0.05 to 10% by weight.

The dosage of the compounds of the present invention may vary widely according to the type of the warm-blooded animal (including human being) to be treated, the route of administration, the severity of symptoms, the diagnosis made by the doctor, and the like. Generally, they may be administered in a daily dose of 0.01 to 5 mg/kg and preferably 0.02 to 2 mg/kg. However, it is a matter of course that they may be administered in doses less than the lower limit of the aforesaid range or greater than the upper limit thereof, depending on the severity of symptoms in the patient and the diagnosis made by the doctor. The aforesaid daily dose may be given at a time or in several divided doses.

EXAMPLES

The present invention is more specifically explained with reference to the following examples and preparation examples.

Example 1

108 mg of 2'-nitrobiphenyl-4-ol was dissolved in 1.5 ml of N,N-dimethyformamide, and a suspension of 120 mg of sodium hydride in 1.5 ml of N,N-dimethyformamide was added thereto under cooling with ice, followed by stirring for 10 minutes under cooling with ice. 367 mg of sulfamoyl chloride was added to this mixture, followed by stirring at room temperature for 3 hours. After water was added to the reaction mixture, the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium. sulfate. After the solvent was distilled off, the resulting crude product was purified by TLC (using a 1:1 mixture of ethyl acetate and hexane as the developing solvent) to obtain 106 mg of 2'-nitrobiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 5.07(2H, br s), 7.30-8.00(8H, m).

MS(m/z): 294(M.sup.+), 215.

Example 2

108 mg of 2'-nitrobiphenyl-4-ol was dissolved in 9.5 ml of methylene chloride, and 312 mg of 2,6-di-tert-butyl-4-methylpyridine and 347 mg of sulfamoyl chloride were successively added thereto under cooling with ice, followed by stirring at room temperature for 5 hours. After water was added to the reaction mixture, the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resulting crude product was purified by TLC (using a 1:1 mixture of ethyl acetate and hexane as the developing solvent) to obtain 149 mg of 2'-nitrobiphenyl-4-yl sulfamate.

Example 3

The procedure of Example 1 was repeated, except that 27 mg of 4'-hydroxy-2-biphenylcarbonitrile was used in place of 2'-nitrobiphenyl-4-ol. Thus, there was obtained 34 mg of 2'-cyanobiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 5.02(2H, br s), 7.34-7.91(8H, m).

MS(m/z): 274(M.sup.+), 195.

Example 4

The procedure of Example 1 was repeated, except that 79 mg of 2'-fluorobiphenyl-4-ol was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 2:1 mixture of hexane and ethyl acetate as the developing solvent) to obtain 81 mg of 2'-fluorobiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 4.95(2H, br s), 7.00-7.71(8H, m).

MS(m/z): 267(M.sup.+), 188.

Example 5

The procedure of Example 1 was repeated, except that 45 mg of 2'-trifluoromethylbiphenyl-4-ol was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 2:1 mixture of hexane and ethyl acetate as the developing solvent) to obtain 24 mg of 2'-trifluoromethylbiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 4.96(2H, br 8), 7.26-7.85(8H, m).

MS(m/z): 317(M.sup.+), 238.

Example 6

The procedure of Example 1 was repeated, except that 64 mg. of 2'-methylbiphenyl-4-ol was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 2:1 mixture of hexane and ethyl acetate as the developing solvent) to obtain 51 mg of 2'-methylbiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 2.26(3H, s), 4.97(2H, br s), 7.10-7.32(4H, m), 7.37(4H, s).

MS(m/z): 263(M.sup.+), 184.

Example 7

The procedure of Example 2 was repeated, except that 37 mg of biphenyl-2,4'-diol was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 10:1 mixture of chloroform and methanol as the developing solvent) to obtain 17 mg of biphenyl-2,4'-diyl disulfamate.

.sup.1 -NMR(CDCl.sub.3, .delta.): 7.14-7.68(8H, m).

MS(m/z): 344(M.sup.+), 265, 186.

Example 8

The procedure of Example 2 was repeated, except that 25 mg of 4'-hydroxy-2-biphenylacetonitrile was used in place of 2'-nitrobiphenyl-4-ol. Thus, there was obtained 30 mg of 2'-cyanomethylbiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 3.64(2H, s), 7.15-7.63(8H, m).

MS(m/z): 288(M.sup.+), 209.

Example 9

The procedure of Example 1 was repeated, except that 79 mg of 3'-fluorobiphenyl-4-ol was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 2:1 mixture of hexane and ethyl acetate as the developing solvent) to obtain 72 mg of 3'-fluorobiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 4.94(2H, br 8), 6.90-7.71(8H, m).

MS(m/z): 267(M.sup.+), 188.

Example 10

The procedure of Example 1 was repeated, except that 49 mg of 3'-nitrobiphenyl-4-ol was used in place of 2'-nitrobiphenyl-4-ol. Thus, there was obtained 40 mg of 3'-nitrobiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 7.33-7.78(5H, m), 7.79-7.98(1H, m), 8.11-8.33(1H, m), 8.33-8.50(1H, m).

MS(m/z): 294(M.sup.+), 215.

Example 11

The procedure of Example 1 was repeated, except that 66 mg of 4'-hydroxy-3-biphenylcarbonitrile was used in place of 2'-nitrobiphenyl-4-ol. Thus, there was obtained 55 mg of 3'-cyanobiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 5.07(2H, br s), 7.34-8.06(8H, m).

MS(m/z): 274(M.sup.+), 195.

Example 12

The procedure of Example 1 was repeated, except that 40 mg of 4'-hydroxy-3-biphenylacetonitrile was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 19:1 mixture of chloroform and methanol as the developing solvent) to obtain 15 mg of 3'-cyanomethylbiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CD.sub.3 OD, .delta.): 3.97(2H, s), 7.34-7.78(8H, m).

MS(m/z): 288(M.sup.+), 209.

Example 13

The procedure of Example 1 was repeated, except that 125 mg of 4'-bromobiphenyl-4-ol was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 2:1 mixture of hexane and ethyl acetate as the developing solvent) to obtain 123 mg of 4'-bromobiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 7.33-7.71(8H, m).

MS(m/z): 329(M.sup.+ +2), 327(M.sup.+), 249, 247.

Example 14

The procedure of Example 1 was repeated, except that 102 mg of 4'-chlorobiphenyl-4-ol was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 2:1 mixture of hexane and ethyl acetate as the developing solvent) to obtain 111 mg of 4'-chlorobiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 4.99(2H, br s), 7.30-7.68(8H, m).

MS(m/z): 285(M.sup.+ +2), 283(M.sup.+), 205, 203.

Example 15

The procedure of Example 1 was repeated, except that 100 mg of 4'-methoxybiphenyl-4-ol was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 2:1 mixture of hexane and ethyl acetate as the developing solvent) to obtain 96 mg of 4'-methoxybiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 3.86(3H, s), 6.98 (2H, d, J=5.8 Hz), 7.35-7.67 (6H, m).

MS(m/z): 279(M.sup.+), 199.

Example 16

The procedure of Example 1 was repeated, except that 108 mg of 4'-nitrobiphenyl-4-ol was used in place of 2'-nitrobiphenyl-4-ol. Thus, there was obtained 108 mg of 4'-nitrobiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 7.33-7.83(6H, m), 8.30(2H, d, J=6.0 Hz).

MS(m/z): 294(M.sup.+), 215.

Example 17

The procedure of Example 1 was repeated, except that 228 mg of methyl 4'-hydroxy-4-biphenylcarboxylate was used in place of 2'-nitrobiphenyl-4-ol. Thus, there was obtained 27 mg of methyl 4'-sulfamoyloxy-4-biphenylcarboxylate.

MS(m/z): 307(M.sup.+), 227.

Example 18

The procedure of Example 1 was repeated, except that 500 mg of 4'-hydroxy-4-biphenylcarbonitrile was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 8:1 mixture of chloroform and ethyl acetate as the developing solvent) to obtain 489 mg of 4'-cyanobiphenyl-4-yl sulfamate.

.sup.1 H-NMR(DMSO-d.sub.6, .delta.): 7.41(2H, d, J=5.5 Hz), 7.86(2H, d, J=5.5 Hz), 7.93(4H, s), 8.06(2H, br s).

MS(m/z): 274(M.sup.+), 195.

Example 19

The procedure of Example 1 was repeated, except that 50 mg of 4'-trifluoromethylbiphenyl-4-ol was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 2:1 mixture of hexane and ethyl acetate as the developing solvent) to obtain 35 mg of 4'-trifluoromethylbiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 4.96(2H, br s), 7.43(2H, d, J=6.0 Hz), 7.62(2H, d, J=6.0 Hz), 7.67(4H, s).

MS(m/z): 317(M.sup.+), 238.

Example 20

The procedure of Example 1 was repeated, except that 13 mg of 4'-hydroxy-4-biphenylacetonitrile was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 19:1 mixture of chloroform and methanol as the developing solvent) to obtain 8 mg of 4'-cyanomethylbiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CD.sub.3 OD, .delta.): 3.93(2H, s), 7.24-7.82(8H, m).

MS(m/z): 288(M.sup.+), 209.

Example 21

The procedure of Example 1 was repeated, except that 50 mg of biphenyl-4,4'-diol was used in place of 2'-nitrobiphenyl-4-ol. Thus, there was obtained 52 mg of biphenyl-4,4'-diyl disulfamate.

.sup.1 H-NMR(CD.sub.3 OD, .delta.): 7.42(4H, d, J=5.8 Hz), 7.66(4H, d, J=5.8 Hz).

MS(m/z): 344(M.sup.+), 265, 186.

Example 22

The procedure of Example 1 was repeated, except that 23 mg of 2-nitrobiphenyl-4,4'-diol was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 10:1 mixture of chloroform and methanol as the developing solvent) to obtain 9 mg of 2-nitrobiphenyl-4,4'-diyl disulfamate.

.sup.1 H-NMR(CD.sub.3 OD, .delta.): 6.97-7.43(7H, m).

MS(m/z): 389(M.sup.+), 310, 231.

Example 23

The procedure of Example 1 was repeated, except that 48 mg of 2',4'-dinitrobiphenyl-4-ol was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 5:1 mixture of chloroform and tetrahydrofuran as the developing solvent) to obtain 42 mg of 2',4'-dinitrobiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 7.32-7.55(4H, m), 7.66(1H, d, J=5.3 Hz), 8.49(1H, dd, J=1.5, 5.3 Hz), 8.74(1H, d, J=1.5 Hz).

MS(m/z): 339(M.sup.+), 260.

Example 24

The procedure of Example 1 was repeated, except that 55 mg of 2,2'-dinitrobiphenyl-4,4'-diol was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 10:1 mixture of chloroform and methanol as the developing solvent) to obtain 12 mg of 2,2'-dinitrobiphenyl-4,4'-diyl disulfamate.

.sup.1 H-NMR(CD.sub.3 OD, .delta.): 7.48(2H, d, J=5.7 Hz), 7.73(2H, dd, J=1.7, 5.7 Hz), 8.19(2H, d, J=1.5 Hz).

MS(m/z): 355(M.sup.+ --SO.sub.2 NH), 276.

Example 25

The procedure of Example 2 was repeated, except that 41 mg of 4'-hydroxy-4-nitro-2-biphenylcarbonitrile was used in place of 2'-nitrobiphenyl-4-ol. Thus, there was obtained 40 mg of 2'-cyano-4'-nitrobiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 7.40-7.73(4H, m), 7.:74(11H, d, J=5.8 Hz), 8.51(1H, dd, J=1.5, 5.5 Hz), 8.65(1H, d, J=1.5 Hz).

MS(m/z): 319(M.sup.+), 240.

Example 26

The procedure of Example 2 was repeated, except that 132 mg of 4'-hydroxy-2-nitro-4-biphenylcarbonitrile was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 10:1 mixture of chloroform and methanol as the developing solvent) to obtain 116 mg of 4'-cyano-2'-nitrobiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 7.33-7.70(4H, m), 7.60(1H, d, J=5.3 Hz), 7.92(1H, dd, J=1, 5.3 Hz), 8.19(1H, d, J=1 Hz).

MS(m/z): 319(M.sup.+), 240.

Example 27

The procedure of Example 2 was repeated, except that 68 mg of 4'-hydroxy-2,4-biphenyldicarbonitrile was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 15:1 mixture of chloroform and methanol as the developing solvent) to obtain 44 mg of 2',4'-dicyanobiphenyl-4-yl sulfamate.

.sup.1 H-NMR(CD.sub.3 OD, .delta.): 7.39-7.78(4H, m), 7.76(1H, d, J=5.5 Hz), 8.06(1H, dd, J=1.7, 5.5 Hz), 8.28(1H, d, J=1.7 Hz).

MS(m/z): 299(M.sup.+), 220.

Example 28

The procedure of Example 1 was repeated, except that 90 mg of 4-[N-(4-hydroxybenzyl)amino]phenol was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 6:1 mixture of chloroform and methanol as the developing solvent) to obtain 49 mg of 4-[N-sulfamoyl-N-(4-sulfamoyloxybenzyl)amino]phenyl sulfamate.

.sup.1 H-NMR(DMSO-d.sub.6, .delta.): 4.77(2H, s), 7.0-8.1(14H, m).

SIMS(m/z): 453(MH.sup.+).

Example 29

The procedure of Example 1 was repeated, except that 22 mg of N-(4-hydroxybenzyl)-N-(4-hydroxyphenyl)methanesulfonamide was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 9:1 mixture of chloroform and methanol as the developing solvent) to obtain 12 mg of 4-[N-methylsulfonyl-N-(4-sulfamoyloxybenzyl)amino]phenyl sulfamate.

.sup.1 H-NMR(DMSO-d.sub.6, .delta.): 3.09(3H, s), 4.89(2H, s), 7.1-8.1(12H, m).

SIMS(m/z): 452(MH.sup.+).

Example 30

The procedure of Example i was repeated, except that 60 mg of N-(4-hydroxybenzyl)-N-(4-hydroxyphenyl)acetamide was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 9:1 mixture of chloroform and methanol as the developing solvent) to obtain 61 mg of 4-[N-acetyl-N-(4-sulfamoyloxybenzyl)amino]-phenyl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 1.90(3H, br s), 4.86(2H, s), 6.9-7.4(8H, m).

HR-SIMS(m/z): 416.0582(MH.sup.+).

Example 31

The procedure of Example 1 was repeated, except that 96 mg of 4-[N-acetyl-N-(4-hydroxybenzyl)amino]phenyl acetate was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 4:1 mixture of chloroform and acetone as the developing solvent) to obtain 57 mg of 4-[N-acetyl-N-(4-sulfamoyloxybenzyl)amino]-phenyl acetate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 1.89(3H, br s), 2.28(3H, s), 4.85(2H, s), 6.9-7.4(8H, m).

MS(m/z): 378(M.sup.+), 341, 151, 109, 107.

Example 32

The procedure of Example 1 was repeated, except that 200 mg of 4-hydroxy-N-(4-hydroxyphenyl)benzamide was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was crystallized from chloroform to obtain 242 mg of 4-[N-(4-sulfamoyloxyphenyl)carbamoyl]-phenyl sulfamate.

.sup.1 H-NMR(DMSO-d.sub.6, .delta.): 7.26(2H, d, J=9 Hz), 7.42(2H, d, J=9 Hz), 7.83(2H, d, J=9 Hz), 7.96(2H, d, J=9 Hz), 8.10(4H, br s), 10.35(1H, br s).

HR-SIMS(m/z): 388.0270(MH.sup.+).

Example 33

The procedure of Example 1 was repeated, except that 231 mg of N-ethyl-4-hydroxy-N-(4-hydroxyphenyl)benzamide was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 9:1 mixture of chloroform and methanol as the developing solvent) to obtain 242 mg of 4-[N-ethyl-N-(4-sulfamoyloxyphenyl)-carbamoyl]phenyl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 1.23(3H, t, J=7 Hz), 3.94(2H, q, J=7 Hz), 6.9-7.4(8H, m).

MS(m/z): 415(M.sup.+), 336, 119.

Example 34

The procedure of Example 1 was repeated, except that 200 mg of 4-hydroxy-N-(4-hydroxyphenyl)-N-methylbenzamide was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 5:1 mixture of chloroform and methanol as the developing solvent) to obtain 200 mg of 4-[N-methyl-N-(4-sulfamoyloxyphenyl)-carbamoyl]phenyl sulfamate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 3.48(3H, s), 6.9-7.4(8H, m).

ESI-MS(m/z): 402(MH.sup.+).

Example 35

The procedure of Example 1 was repeated, except that 200 mg of 4-hydroxy-N-(3-hydroxyphenyl)benzamide was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 5:1 mixture of chloroform and methanol as the developing solvent) to obtain 185 mg of 4-[N-(3-sulfamoyloxyphenyl)carbamoyl]-phenyl sulfamate.

.sup.1 H-NMR(DMSO-d.sub.6, .delta.): 6.9-8.2(12H, m), 10.44(1H, br 8).

ESI-MS(m/z): 388(MH.sup.+).

Example 36

The procedure of Example 1 was repeated, except that 222 mg of 4-hydroxy-N-(3-hydroxyphenyl)-N-methylbenzamide was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was purified by TLC (using a 9:1 mixture of chloroform and methanol as the developing solvent) to obtain 188 mg of 4-[N-methyl-N-(3-sulfamoyloxyphenyl)-carbamoyl]phenyl sulfate.

.sup.1 H-NMR(CDCl.sub.3, .delta.): 3.51(3H, s), 6.7-8.5(8H, m).

ESI-MS(m/z): 402(MH.sup.+).

Example 37

The procedure of Example 2 was repeated, except that 83 mg of N'-acetyl-4-hydroxy-N-phenylbenzohydrazide was used in place of 2'-nitrobiphenyl-4-ol. The resulting crude product was crystallized from ethyl acetate to obtain 53 mg of 4-(N'-acetyl-N-phenylhydrazino-carbonyl)phenyl sulfamate.

.sup.1 H-NMR(CD.sub.3 OD, .delta.): 1.90(3H, s), 7.1-7.7(9H, m).

MS(m/z): 270, 200, 150, 121.

Example 38

The procedure of Example 2 was repeated, except that 568 mg of 4[-N-(4-hydroxybenzyl)-N-(1,2,4-triazol-4-yl)amino]benzonitrile was used in place of 2'-nitrobiphenyl-4-ol, and 30 ml of N,N-dimethylformamide was used in place of methylene chloride. The resulting crude product was purified by Silica gel column chromatography (using a 10:1 mixture of chloroform and methanol as the eluent) to obtain 512 mg of 4-[N-(4-cyano-phenyl)-N-(1,2,4-triazol-4-yl)aminomethyl]phenyl sulfamate.

.sup.1 H-NMR(DMSO-d.sub.6, .delta.): 5.08(2H, s), 6.74(2H, d, J=9.2 Hz), 7.23(2H, d, J=8.8 Hz), 7.39(2H, d, J=8.8 Hz), 7.74(2H, d, J=9.0 Hz), 7.96(2H, br s), 8.80(2H, s).

MS(m/z): 291(M+--SO.sub.2 NH), 185.

Example 39

The procedure of Example 2 was repeated, except that 2.81 g of N-(4-cyanophenyl)-4-hydroxy-N-(1,2,4-triazol-4-yl)benzamide was used in place of 2'-nitrobiphenyl-4-ol, and 28 ml of N,N-dimethylformamide was used in place of methylene chloride. The resulting crude product was purified by silica gel column chromatography (using a 10:1 mixture of chloroform and methanol as the eluent) to obtain 1.07 g of 4-[N-(4-cyanophenyl)-N-(1,2,4-triazol-4-yl)carbamoyl]phenyl sulfamate.

.sup.1 H-NMR(DMSO-d.sub.6, .delta.): 7.29(2H, d, J=8.8 Hz), 7.58(2H, d, J=8.8 Hz), 7.62 (2H, d, J=8.6 Hz), 7.90(2H, d, J=8.8 Hz), 8.13(2H, br s), 9.11 (2H, s).

MS(m/z): 384(M.sup.+), 185.

Example 40

32 mg of 4-formylphenyl sulfamate was added to a mixture composed of 11.5 .mu.l of aniline, 0.2 ml of ethanol, 27 mg of sodium acetate, 84 .mu.l of aceti