Chemoprotective isothiocyanates

• US 5,411,986 A
• Filed: 03/12/1993
• Issued: 05/02/1995
• Est. Priority Date: 03/12/1993
• Status: Expired due to Term

• Current Assignee: Cheon-Gyu Cho, Gary H. Posner, Paul Talalay, Yuesheng Zhang
• Original Assignee: Johns Hopkins University
• Inventors: Cho, Cheon-Gyu, Talalay, Paul, Posner, Gary H., Zhang, Yuesheng
• Primary Examiner(s): Richter, Johann
• Assistant Examiner(s): McKane, Joseph K.
• Application Number:
  US08/030,610
• Time in Patent Office: 781 Days
• Field of Search: 558/17, 514/514
• US Class Current: 514/514
• CPC Class Codes: A61K 31/145 having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2) isothiourea A61K31/155
• CPC Class Codes: A61K 31/26 Cyanate or isocyanate esters; Thiocyanate or isothiocyanate esters
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: C07C 331/20 of a saturated carbon skeleton
• CPC Class Codes: C07C 331/24 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 331/26 having isothiocyanate groups bound to carbon atoms of rings other than six-membered aromatic rings
• CPC Class Codes: C07C 331/28 having isothiocyanate groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07F 9/4006 Esters of acyclic acids which can have further substituents on alkyl

Abstract

Sulforaphane has been isolated and identified as a major and very potent phase II enzyme inducer in broccoli (Brassica oleracea italica). Sulforaphane is a monofunctional inducer, inducing phase II enzymes selectively without the induction of aryl hydrocarbon receptor-dependent cytochromes P-450 (phase I enzymes). Analogues differing in the oxidation state of sulfur and the number of methylene groups were synthesized, and their inducer potencies were measured. Sulforaphane is the most potent of these analogues. Other analogues having different substituent groups in place of the methylsulfinyl group of sulforaphane were also synthesized and assessed. Of these, the most potent are 6-isothiocyanato-2-hexanone and exo-2-acetyl-6-isothiocyanatonorbornane.

Claims

1. A pharmaceutical composition comprising an active ingredient which is sulforaphane ((-)1-isothiocyanato-(4R)-(methylsulfinyl)butane) (CAS 4478-93-7) or an analogue thereof, said analogue being selected from the group consisting of:

6-isothiocyanato-2-hexanone (GHP

     1105);

exo-2-acetyl-6-isothiocyanatonorbornane (GHP

     1066);

exo-2-isothiocyanato-6-methylsulfonylnorbornane(GHP

     1068);

6-isothiocyanato-2-hexanol (GHP 1106;

1-isothiocyanato-4-dimethylphosphonylbutane (GHP

     1078);

exo-2-(1'"'"'-hydroxyethyl)-5-isothiocyanatonorbornane (GHP

     1075);

exo-2-acetyl-5-isothiocyanatonorbornane (GHP

     1067);

1-isothiocyanato-5-methylsulfonylpentane (GHP

     1003); and

cis- or trans-3-(methylsulfonyl)cyclohexylmethylisothiocyanate (GHP 1079 or

     1080).

2. The pharmaceutical composition of claim 1 wherein said active ingredient is sulforaphane.

3. The pharmaceutical composition of claim 1 wherein said active ingredient is selected from the group consisting of:

6-isothiocyanato-2-hexanone (GHP

     1105);

exo-2-acetyl-6-isothiocyanatonorbornane (GHP

     1066);

exo-2-isothiocyanato-6-methylsulfonylnorbornane (GHP

     1068);

6-isothiocyanato-2-hexanol (GHP

     1106);

1-isothiocyanato-4-dimethylphosphonylbutane (GHP

     1078);

exo-2-(1'"'"'-hydroxyethyl)-5-isothiocyanatonorbornane (GHP

     1075);

exo-2-acetyl-5-isothiocyanatonorbornane (GHP

     1067);

1-isothiocyanato-5-methylsulfonylpentane (GHP

     1003); and

cis- or trans-3-(methylsulfonyl)cyclohexylmethylisothiocyanate (GHP 1079 or

     1080).

4. The pharmaceutical composition of claim 1 further comprising a pharmaceutically acceptable excipient.

5. A compound consisting of:

1-isothiocyanato-5-methylsulfonylpentane (CH₃ --SO₂ --(CH₂)₅ --NCS) ((GHP

     1003).

6. A compound consisting of:

6-isothiocyanato-2-hexanone (CH₃ CO(CH₂)₄ NCS) (GHP

     1105).

7. A compound consisting of:

exo-2-acetyl-6-isothiocyanatonorbornane (GHP

     1066).

8. A compound consisting of:

exo-2-isothiocyanato-6-methylsulfonylnorbornane (GHP

     1068).

9. A compound consisting of:

6-isothiocyanato-2-hexanol (GHP

     1106).

10. A compound consisting of:

1-isothiocyanato-4-dimethylphosphonylbutane (GHP

     1078).

11. A compound consisting of:

exo-2-(1'"'"'-hydroxyethyl)-5-isothiocyanatonorbornane (GHP

     1075).

12. A compound consisting of:

exo-2-acetyl-5-isothiocyanatonorbornane (GHP

     1067).

13. A compound consisting of:

cis-or trans-3-(methylsulfonyl)cyclohexylmethylisothiocyanate (GHP 1079 or

     1080).

14. A method for suppressing the formation of chemically-induced mammary tumors or hepatomas, comprising:

administering to a mammal a chemoprotective composition consisting essentially of sulforaphane ((-)1-isothiocyanato-(4R)-(methylsulfinyl)butane) or an analogue thereof, said analogue being selected from the group consisting of;

6-isothiocyanato-2-hexanone (GHP

     1105);

exo-2-acetyl-6-isothiocyanatonorbornane (GHP

     1066);

exo-2-isothiocyanato-6-methylsulfonylnorbornane (GHP

     1068);

6-isothiocyanato-2-hexanol (GHP

     1106);

1-isothiocyanato-4-dimethylphosphonylbutane (GHP

     1078);

exo-2-(1'"'"'-hydroxyethyl)-5-isothiocyanatonorbornane (GHP

     1075);

exo-2-acetyl-5-isothiocyanatonorbornane (GHP

     1067);

1-isothiocyanato-5-methylsulfonylpentane (GHP

     1003); and

cis- or trans-3-(methylsulfonyl)cyclohexylmethylisothiocyanate (GHP 1079 or

     1080), in an amount effective in producing a mammary tumor or hepatoma formation suppressing effect.