Chemoprotective isothiocyanates

• US RE36,784 E
• Filed: 05/02/1997
• Issued: 07/18/2000
• Est. Priority Date: 03/12/1993
• Status: Expired due to Term

• Current Assignee: US Bank National Association (US Bancorp)
• Original Assignee: Johns Hopkins University
• Inventors: Zhang, Yuesheng, Talalay, Paul, Posner, Gary H., Cho, Cheon-Gyu
• Primary Examiner(s): McKane, Joseph
• Assistant Examiner(s): SACKEY, EBENEZER O
• Application Number:
  US08/850,387
• Time in Patent Office: 1,173 Days
• Field of Search: 514/514, 514/515, 558/17, 426/648, 426/547, 424/94.1, 424/615, 424/655, 424/49, 424/52
• US Class Current: 424/94.1
• 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.]. .Iadd.an analogue of .Iaddend.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

14. excipient. .Iaddend..Iadd.22. The composition of claim 15, wherein said active ingredient is sulforaphane ((-)-isothiocyanato-(4R)-(methylsulfinyl)butane). .Iaddend..Iadd.23. The method of claim 17, wherein said oral dose form is a dietary supplement. .Iaddend..Iadd.24. The composition of claim 1, wherein said composition is in oral, topical or parenteral dose form. .Iaddend..Iadd.25. The composition of claim 15, wherein said composition is in oral, topical or parenteral dose form. .Iaddend..Iadd.26. The composition of claim 1, wherein said composition is a dietary supplement. .Iaddend..Iadd.27. The composition of claim 15, wherein said composition is a dietary supplement. .Iaddend..Iadd.28. The composition of claim 1, wherein said composition is incorporated into a food product. .Iaddend..Iadd.29. The composition of claim 15, wherein said composition is incorporated into a food product. .Iaddend..Iadd.30. The composition of claim 1, wherein said composition is a food supplement or food additive. .Iaddend..Iadd.31. The composition of claim 15, wherein said composition is a food supplement or food additive. .Iaddend..Iadd.32. The composition of claim 24, wherein said dosage form

2. comprising a pharmaceutically acceptable excipient..].5. A compound consisting of:

1-isothiocyanato-5-methylsulfonylpentane (CH₃

3. --SO₂ --(CH₂)₅ --NCS) .[.((GHP 1003).].. 6. A compound consisting of:

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

4. NCS) .[.(GHP 1105).].. 7. A compound consisting of:

5. exo-2-acetyl-6-isothiocyanatonorbornane .[.(GHP 1066).].. 8. A compound consisting of:

exo-2-isothiocyanato-6-methylsulfonylnorbornane .[.(GHP

6. 1068).].. 9. A compound consisting of:

6-isothiocyanato-2-hexanol .[.(GHP

7. 1106).].. 10. A compound consisting of:

8. 1-isothiocyanato-4-dimethylphosphonylbutane .[.(GHP 1078).].. 11. A compound consisting of:

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

9. [.(GHP 1075).].. 12. A compound consisting of:

10. exo-2-acetyl-5-isothiocyanatonorbornane .[.(GHP 1067).].. 13. A compound consisting of:

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

11. 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.]. .Iadd.comprising an analogue of .Iaddend.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

12. formation suppressing effect. .Iadd.15. A composition comprising an active ingredient which is sulforaphane ((-)1-isothiocyanato-(4R)-(methylsulfinyl)(butane) or an analogue thereof, said analogue being selected from the group consisting of:

6-isothiocyanato-2-hexanone;

exo-2-acetyl-6-isothiocyanatonorbornane;

exo-2-isothiocyanato-6-methylsulfonylnorbornane;

6-isothiocyanato-2-hexanol;

1-isothiocyanato-4-dimethylphosphonylbutane;

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

exo-2-acetyl-5-isothiocyanatonorbornane;

1-isothiocyanato-5-methylsulfonylpentane; and

cis- or trans-3-(methylsulfonyl)cyclohexylmethylisothiocyanate, and a suitable

16. Iaddend..Iadd. 7. The method of promoting human health comprising the steps of:

(a) extracting sulforaphane or an analogue thereof from a natural source; and

(b) providing said sulforaphane or analogue thereof to a human. .Iaddend.

13. excipient. .Iaddend..Iadd.16. A method of chemoprotection comprising the steps of:

(a) synthesizing sulforaphane or an isothiocyanate analogue thereof, or purifying sulforaphane or an isothiocyanate analogue thereof from a natural source; and

(b) providing said sulforaphane or isothiocyanate analogue thereof to a human,

wherein said isothiocyanate analog comprises an isothiocyanate moiety and a polar functional group linked to the isothiocyanate moiety by a chain of one or more carbon atoms, and induces quinone reductase activity. .Iaddend..Iadd.17. The method according to claim 16, wherein said sulforaphane or isothiocyanate analogue thereof is administered in oral, topical or parenteral dose form. .Iaddend..Iadd.18. The method according to claim 16, wherein said sulforaphane or isothiocyanate analogue thereof is provided as a food, food supplement, or food additive. .Iaddend..Iadd.19. The method according to claim 17, wherein said oral dose form is a pharmaceutical. .Iaddend..Iadd.20. The method according to claim 16, wherein said sulforaphane or isothiocyanate analogue thereof is administered in topical or parenteral dose form. .Iaddend..Iadd.21. A method for suppressing the formation of chemically-induced mammary tumors or hepatomas, comprising;

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

6-isothiocyanato-2-hexanone;

exo-2-acetyl-6-isothiocyanatonorbornane;

exo-2-isothiocyanato-6-methylsulfonylnorbornane;

6-isothiocyanato-2-hexanol;

1-isothiocyanato-4-dimethylphosphonylbutane;

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

exo-2-acetyl-5-isothiocyanatonorbornane;

1-isothiocyanato-5-methylsulfonylpentane; and

cis- or trans-3-(methylsulfonyl)cyclohexylmethylisothiocyanate, and a suitable

15. is a pharmaceutical. .Iaddend..Iadd.33. The composition of claim 25, wherein said dosage form is a pharmaceutical. .Iaddend..Iadd.34. A method of chemoprotection comprising the steps of:

(a) extracting sulforaphane or an isothiocyanate analogue thereof from a natural source; and

(b) providing said sulforaphane or isothiocyanate analogue thereof to a human,

wherein said isothiocyanate analog comprises an isothiocyanate moiety and a polar functional group linked to the isothiocyanate moiety by a chain of one or more carbon atoms, and induces quinone reductase activity. .Iaddend..Iadd.35. A method of chemoprotection comprising administering to said human a composition comprising an active ingredient which is sulforaphane ((-)-1-isothiocyanato-(4R)-(methylsulfinyl)butane) or an analogue thereof, said analogue being selected from the group consisting of;

6-isothiocyanato-2-hexanone;

exo-2-acetyl-6-isothiocyanatonorbornane;

exo-2-isothiocyanato-6-methylsulfonylnorbornane;

6-isothiocyanato-2-hexanol;

1-isothiocyanato-4-dimethylphosphonylbutane;

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

exo-2-acetyl-5-isothiocyanatonorbornane;

1-isothiocyanato-5-methylsulfonylpentane; and

cis- and trans-3-(methylsulfonyl)cyclohexylmethylisothiocyanate, and a suitable excipient. .Iaddend..Iadd.36. A method of chemoprotection comprising administering to said human a composition comprising an active ingredient which is an analogue of sulforaphane ((-)-1-isothiocyanato-(4R)-(methylsulfinyl)butane) selected from the group consisting of 6-isothiocyanato-2-hexanone, exo-2-acetyl-6-isothiocyanatonorbornane, exo-2-isothiocyanato-6-methylsulfonylnorbornane, 6-isothiocyanato-2-hexanol;

1-isothiocyanato-4-dimethylphosphonylbutane, exo-2-(1'"'"'-hydroxyethyl)-5-isothiocyanatonorbornane, exo-2-acetyl-5-isothiocyanatonorbornane, 1-isothiocyanato-5-methylsulfonylpentane, and cis- or trans-3-(methylsulfonyl)cyclohexylmethylisothiocyanate. .Iaddend..Iadd.37. A method of stimulating mammalian enzymes involved in detoxification of carcinogens, comprising administering to said mammal a chemoprotective composition comprising sulforaphane ((-)1-isothiocyanato-(4R)-(methylsulfinyl)butane) or an analogue thereof, said analogue being selected from the group consisting of;

6-isothiocyanato-2-hexanone;

exo-2-acetyl-6-isothiocyanatonorbornane;

exo-2-isothiocyanato-6-methylsulfonylnorbornane;

6-isothiocyanato-2-hexanol;

1-isothiocyanato-4-dimethylphosphonylbutane;

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

exo-2-acetyl-5-isothiocyanatonorbornane;

1-isothiocyanato-5-methylsulfonylpentane; and

cis- or trans-3-(methylsulfonyl)cyclohexylmethylisothiocyanate, and a suitable excipient. .Iaddend..Iadd.38. A method of stimulating mammalian enzymes involved in detoxification of carcinogens, comprising administering to said mammal a composition comprising an active ingredient which is an analogue of sulforaphane ((-)1-isothiocyanato-(4R)-(methylsulfinyl)butane) selected from the group consisting of 6-isothiocyanato-2-hexanone, exo-2-acetyl-6-isothiocyanatonorbornane, exo-2-isothiocyanato-6-methylsulfonylnorbornane, 6-isothiocyanato-2-hexanol, 1-isothiocyanato-4-dimethylphosphonylbutane, exo-2-(1'"'"'-hydroxyethyl)-5-isothiocyanatonorbornane, exo-2-acetyl-5-isothiocyanatonorbornane, 1-isothiocyanato-5-methylsulfonylpentane, and cis- or trans-3-(methylsulfonyl)cyclohexylmethylisothiocyanate. .Iaddend..Iadd.39. A method of protecting a mammal against the toxic and neoplastic effects of carcinogens, comprising administering to said mammal a chemoprotective composition comprising sulforaphane ((-)-isothiocyanato-(4R)-(methylsulfinyl)butane) or an analogue thereof, said analogue being selected from the group consisting of;

6-isothiocyanato-2-hexanone;

exo-2-acetyl-6-isothiocyanatonorbornane;

exo-2-isothiocyanato-6-methylsulfonylnorbornane;

6-isothiocyanato-2-hexanol;

1-isothiocyanato-4-dimethylphosphonylbutane;

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

exo-2-acetyl-5-isothiocyanatonorbornane;

1-isothiocyanato-5-methylsulfonylpentane; and

cis- or trans-3-(methylsulfonyl)cyclohexylmethylisothiocyanate, and a suitable excipient. .Iaddend..Iadd.40. A method of protecting a mammal against the toxic and neoplastic effects of carcinogens, comprising administering to said mammal a composition comprising an active ingredients which is an analogue of sulforaphane ((-)1-isothiocyanato-(4R)-(methylsulfinyl)butane) selected from the group consisting of 6-isothiocyanato-2-hexanone, exo-2-acetyl-6-isothiocyanatonorbornane, exo-2-isothiocyanato-6-methylsulfonylnorbornane, 6-isothiocyanato-2-hexanol;

1-isothiocyanato-4-dimethylphosphonylbutane, exo-2-(1'"'"'-hydroxyethyl)-5-isothiocyanatonorbornane, exo-2-acetyl-5-isothiocyanatonorbornane, 1-isothiocyanato-5-methylsulfonylpentane, and cis- or trans-3-(methylsulfonyl)cyclohexylmethylisothiocyanate. .Iaddend..Iadd.41. A method of inducing phase II xenobiotic metabolizing enzymes, comprising administering to said mammal a chemoprotective composition comprising sulforaphane ((-)1-isothiocyanato-(4R)-(methylsulfinyl)butane) or an analogue thereof, said analogue being selected from the group consisting of;

6-isothiocyanato-2-hexanone;

exo-2-acetyl-6-isothiocyanatonorbornane;

exo-2-isothiocyanato-6-methylsulfonylnorbornane;

6-isothiocyanato-2-hexanol;

1-isothiocyanato-4-dimethylphosphonylbutane;

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

exo-2-acetyl-5-isothiocyanatonorbornane;

1-isothiocyanato-5-methylsulfonylpentane; and

cis- or trans-3-(methylsulfonyl)cyclohexylmethylisothiocyanate, and a suitable excipient. .Iaddend..Iadd.42. A method of inducing phase II xenobiotic metabolizing enzymes, comprising administering to said mammal a composition comprising an active ingredient which is an analogue of sulforaphane ((-)1-isothiocyanato-(4R)-(methylsulfinyl)butane) selected from the group consisting of 6-isothiocyanato-2-hexanone, exo-2-acetyl-6-isothiocyanatonorbornane;

exo-2-isothiocyanato-6-methylsulfonylnorbornane, 6-isothiocyanato-2-hexanol;

1-isothiocyanato-4-dimethylphosphonylbutane, exo-2-(1'"'"'-hydroxyethyl)-5-isothiocyanatonorbornane, exo-2-acetyl-5-isothiocyanatonorbornane, 1-isothiocyanato-5-methylsulfonylpentane, and cis- or trans-3-(methylsulfonyl)cyclohexylmethylisothiocyanate. .Iaddend..Iadd.43. The method according to claim 16, wherein said isothiocyanate analog is selected from the group consisting of 6-isothiocyanato-2-hexanone, exo-2-acetyl-6-isothiocyanatonorbornane, exo-2-isothiocyanato-6-methylsulfonylnorbornane, 6-isothiocyanato-2-hexanol;

1-isothiocyanato-4-dimethylphosphonylbutane, exo-2-(1'"'"'-hydroxyethyl)-5-isothiocyanatonorbornane, exo-2-acetyl-5-isothiocyanatonorbornane, 1-isothiocyanato-5-methylsulfonylpentane, and cis- or trans-3-(methylsulfonyl)cyclohexylmethylisothiocyanate. .Iaddend..Iadd.44. The method according to claim 34, wherein said isothiocyanate analog is selected from the group consisting of 6-isothiocyanato-2-hexanone, exo-2-acetyl-6-isothiocyanatonorbornane, exo-2-isothiocyanato-6-methylsulfonylnorbornane, 6-isothiocyanato-2-hexanol;

1-isothiocyanato-4-dimethylphosphonylbutane, exo-2-(1'"'"'-hydroxyethyl)-5-isothiocyanatonorbornane, exo-2-acetyl-5-isothiocyanatonorbornane, 1-isothiocyanato-5-methylsulfonylpentane, and cis- or trans-3-(methylsulfonyl)cyclohexylmethylisothiocyanate. .Iaddend..Iadd.45. A composition comprising an isothiocyanate analogue of sulforaphane ((-)1-isothiocyanato(4R)-(methylsulfinyl)butane), wherein said isothiocyanate analog comprises an isothiocyanate moiety and a polar functional group linked to the isothiocyanate moiety by a chain of one or more carbon atoms, and induces quinone reductase activity. .Iaddend..Iadd.46. A composition comprising an active ingredient which is sulforaphane ((-)1-isothiocyanato-(4R)-(methylsulfinyl)butane) or an isothiocyanate analogue thereof and a suitable excipient, wherein said isothiocyanate analog comprises an isothiocyanate moiety and a polar functional group linked to the isothiocyanate moiety by a chain of one or more carbon atoms, and induces quinone reductase activity.