Potassium channel activators and their use

• US 6,342,517 B1
• Filed: 12/03/1999
• Issued: 01/29/2002
• Est. Priority Date: 12/04/1998
• Status: Expired due to Fees

• Current Assignee: Cambridge Bioclinical Limited
• Original Assignee: Cambridge Bioclinical Limited
• Inventors: Hartmann, Michael, Kealey, George Terence Evelyn, Towart, Robertson, Esch, Peter, Rovenszky, Franz, Christoph, Thomas
• Primary Examiner(s): Lambkin, Deborah C.
• Application Number:
  US09/454,029
• Time in Patent Office: 788 Days
• Field of Search: 548/526, 514/422, 514/440, 514/436, 549/39, 549/22
• US Class Current: 514/422
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

Novel thienopyran compounds are disclosed, useful as anti-hypertensive agents and for asthma treatment. One group of the compounds has a heterocyclic ring spiro-connected at the 7-position of the thienopyran ring structure. Use of thienopyran compounds in hair growth modulation is described.

Claims

1. A thienopyran compound having one of the formulas I, II and III

wherein

X is H or an electron-withdrawing group,

Y is an alicyclic or heterocyclic ring spiro-connected to the thienopyran ring at the position indicated by Y, the ring Y being saturated or mono-unsaturated and being substituted or unsubstituted,

Z is selected from hydrogen, hydroxy and alkoxy.

2. A thienopyran compound according to claim 1 wherein z is M.

3. A thienopyran compound according to claim 1 wherein X is an electron-withdrawing group selected from NO₂, CN, halogen, halogenated alkyl, alkanoyl (C_1-4), halogenated alkanoyl (C_1-4) benzoyl, acylamino (C_2-4), alkoxycarbonyl (C_1-4), CHO, COOH, COOR where R is C_1-4, CH═

NOH, CONH₂ CON(R′

)₂ or NHCOR′

where R′

is alkyl (C_1-4), alkoxy (C_1-4) or phenyl, oxophosphorus and oxosulphur groups and

4. A thienopyran according to claim 1 wherein X is selected from CN, halogenated lower alkyl, oxophosphorus and oxosulphur groups, oxocarbon groups and —

CH═

NOH.

5. A thienopyran according to claim 4 wherein X is CN or —

SO₂—

Ph where Ph is substituted or unsubstituted phenyl.

6. A thienopyran according to claim 1 wherein ring Y is

wherein Q is selected from saturated and mono-unsaturated carbon chains of 2-4 carbon atoms, and A and B fulfil one of the following:

(a) both being carbon atoms, (b) one being S, SO or SO₂ and the other a carbon atom, (c) each being S, SO or SO₂, (d) one being NR″

where R″

is hydrogen or alkyl and the other being a carbon atom, (e) each being NR″

where R″

is hydrogen or alkyl; and

each carbon atom of the ring Y is unsubstituted or substituted by one of alkyl, halogen or hydroxy or is a member of a carbonyl group or an epoxy ring.

7. A thienopyran compound according to claim 1 wherein Y is of the formula

wherein S₁ is selected from >

S, >

SO and >

SO₂, S₂ is part of a carbon chain with Q or is selected from >

S, >

SO and >

SO₂, and Q is selected from saturated and unsaturated carbon chains of 2-4 C atoms, each carbon atom of the heterocyclic ring being one of unsubstituted and substituted by one of alkyl, halogen and hydroxy, or being a member of one of a carbonyl group and an epoxy ring.

8. A thienopyran compound according to claim 7 wherein Y is selected from the following:

9. A thienopyran compound according to claim 8 having the formula I.

10. A pharmaceutical preparation comprising a thienopyran compound according to claim 1.

11. A composition for administration to a human or other mammal, comprising as active ingredient a thienopyran compound according to claim 1.

12. A composition according to claim 11 effective for hair growth modulation in a human or other mammal.

13. A method of modulation of hair growth in a human or other mammal, comprising topical application of a thienopyran compound according to claim 1.

14. A method of modulation of hair growth in a human or other mammal, comprising topical application of a thienopyran compound which has activity of hair growth modulation in an amount effective to provide hair growth modulation.

15. A method of modulation of hair growth in a human or other mammal, comprising topical application of an effective amount of at least one thienopyran compound having the formula I, II or III

and A₁ and A₂ are selected from hydrogen, nitro, cyano, trifluoromethyl, halogen, lower alkyl (C_1-4), alkanoyl (C_2-4), substituted alkyl (C_1-4) and substituted alkanoyl (C_2-4), wherein the substituent is halogen;

benzoyl, substituted benzoyl, wherein the substituent is selected from bromo, chloro, iodo, alkyl (C_1-4), alkoxy (C_1-4), acyl (C_2-4), nitro, cyano and trifluoromethyl, acylamino (C_2-4), alkoxy carbonyl (C_1-4), CHO, COOH;

CH═

NOH, CONNH₂, COOR, CON(R)₂ and NHCOR wherein R is alkyl (C_1-4), alkoxy (C_1-4), phenyl or substituted phenyl wherein the substituent is selected bromo, chloro, iodo, lower alkyl, lower alkoxy, nitro, cyano, trifluoromethyl and acyl (C_2-4);

oxophosphorus and oxosulphur groups; and

A₃ and A₄ are selected from hydrogen, hydroxy, alkanoyl (C_2-5), alkyl (C_1-4), cycloalkyl (C_3-6), cycloalkyl carbonyl (C_3-6), pyridyl carbonyl, benzoyl, substituted benzoyl wherein the substituent is selected from bromo, chloro, iodo, alkyl (C_1-4), alkoxy (C_1-4), acyl (C_2-4), nitro, cyano and trifluoromethyl, or A₃A₄N together are a heterocyclic ring selected from a pyrrole, pyrrolidine or piperidine ring, a (C_3-9) lactam selected from the group consisting of isoindolone, pyrrolidinone, piperidinone, pyridinone, pyrazinone, and glycine anhydride, or substituted (C_3-9) lactam;

A₅ is hydrogen or together with A₆ forms a double bond;

M is CH or taken together with A₆ is carbonyl;

A₆ is hydrogen, hydroxy, alkoxy (C_1-6), alkanoyloxy (C_2-7), benzoyloxy, substituted benzoyloxy; and

A₇ and A₈ are hydrogen or alkyl (C_1-4) or together form a ring having 5-8 carbon atoms; and

optical isomers thereof.

16. A composition for topical administration to a human or other mammal, comprising as active ingredient a thienopyran compound having one of the formulas I, II and III

wherein

X in H or an electron-withdrawing group selected from —

CN, halogenated alkyl, oxophosphorus or oxosulphur groups, oxocarbon groups, —

CH═

NOH and

 

and A is one of

wherein B is a saturated or unsaturated carbon chain of 2-4 C atoms of which each carbon atom is unsubstituted or substituted by one of alkyl, halogen and hydroxy, or is a member of an epoxy ring, and at least one dermally acceptable formulating ingredient.

17. A composition according to claim 16, therein X is —

CN.

18. A composition according to claim 16, wherein A is selected from the following:

24. A composition according to claim 16 effective for hair growth modulation in a human or other mammal.

19. A composition for topical administration to a human or other mammal, comprising as active ingredient a thienopyran compound having one of the formulas I, II and III

wherein

X is selected from oxophosphorus and oxosulphur groups, and

D is one of

wherein B is a saturated or unsaturated carbon chain of 2-4 C atoms of which each carbon atom is unsubstituted or substituted by one of alkyl, halogen and hydroxy, or is a member of an epoxy ring, and at least one dermally acceptable formulating ingredient.

20. A composition according to claim 19, wherein X is —

SO₂—

Ph where Ph is substituted or unsubstituted phenyl.

21. A composition according to claim 19, wherein D is

25. A composition according to claim 19 effective for hair growth modulation in a human or other mammal.

22. A method of modulation of hair growth in a human or other mammal, comprising topical application of a thienopyran compound having one of the formulas I, II and III

wherein

X is H or an electron-withdrawing group selected from —

CN, halogenated alkyl, oxophosphorus or oxosulphur groups, oxocarbon groups, —

CH═

NOH and

A is one of

wherein B is a saturated or unsaturated carbon chain of 2-4 C atoms of which each carbon atom is unsubstituted or substituted by one of alkyl, halogen and hydroxy, or is a member of an epoxy ring, and at least one dermally acceptable formulating ingredient.

23. A method of modulation of hair growth in a human or other mammal, comprising topical application of a thienopyran compound having one of the formulas I, II and III

wherein

X is selected from oxophosphorus and oxosulphur groups, and

D is one of

wherein B is a saturated or unsaturated carbon chain of 2-4 C atoms of which each carbon atom in unsubstituted or substituted by one of alkyl, halogen and hydroxy, or is a member of an epoxy ring, and at least one dermally acceptable formulating ingredient.