Potassium channel activators and their use

Details Potassium channel activators and their use Potassium channel activators and their use

1999-12-03

2002-01-29

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S440000, C514S436000, C548S526000, C549S039000, C549S022000

Reexamination Certificate

active

06342517

ABSTRACT:

TECHNICAL FIELD
This invention relates to potassium channel activators in the form of thienopyran compounds, preparations and compositions containing them, and their use in mammalian hair growth modulation.
BACKGROUND OF THE INVENTION
Potassium channels (K
+
channels) are important cell function regulatory sites. There appears to be a diversity of such channels. Interest in them as sites of therapeutic intervention has increased in recent years (Cook, N. S., Potassium Channels: structure, classification, function and therapeutic potential, Ellis Horwood Ltd., 1990).
Compounds which act as potassium channel activators (potassium channel openers) are known. Research in the area was stimulated by the discovery of cromakalim (described in EP-A-76075), which has a benzopyran-based structure, but the molecular details which cause the activity are not yet elucidated.
U.S. Pat. No. 5,077,307 discloses certain potassium channel activators having a thienopyran ring structure. Specifically, the following two compounds are disclosed:
where X is —CN and —CONH
2
. The hydroxy and oxopyrrolidinyl groups at the 6,7 positions have a trans orientation. The first of these (with X=CN) is disclosed in U.S. Pat. No. 5,077,307 in its racemic form and as each of its enantiomers. The racemic form is referred to below as compound 11901, and the (−)-enantiomer as compound 11903.
Other substituted thienopyrans useful as anti-hypertensive agents and for other purposes are disclosed in U.S. Pat No. 5,284,857.
SUMMARY OF THE INVENTION
The object of the invention in to provide new and useful compounds which have potassium channel activating. activity.
According to the invention in a first aspect there is provided a thienopyran compound having the formula I, II or 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.
Preferably, X is H or an electron-withdrawing group selected from NO
2
, 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, CONH
2
CON(R′)
2
or NHCOR′ where R′ is alkyl (C
1-4
), alkoxy (C
1-4
) or phenyl, oxophosphorus and oxosulphur groups and
More preferably, X is selected from —CN, halogenated alkyl (preferably of 1-4 C atoms), oxophosphorus or oxosulphur groups (preferably —SO
2
R
1
or PO(OR
2
), where R
1
is substituted or unsubstituted phenyl, pyridyl or thienyl and each R
2
is H or alkyl of 1-4 C atoms), oxocarbon groups (e.g. —CHO, —CONR
3
2
, —COOR
3
, wherein each R
3
is H or alkyl of 1-4 C atoms) and —CH═NOH,
Ring Y is preferably
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 SO
2
, 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.
More preferably Y is of the formula
wherein
S
1
is >S, >SO or SO
2
and S
2
is part of a carbon chain with Q or is >S, >SO or >SO
2
, and Q is a saturated or unsaturated (preferably mono-unsaturated) carbon chain of 2-4 C atoms, each carbon atom of the heterocyclic ring being unsubstituted or substituted by alkyl (preferably of 1-4 C atoms), halogen or hydroxy, or is a member of a carbonyl group or an epoxy ring, and
Z is hydrogen, hydroxy or alkoxy (preferably of 1-4 C atoms).
Preferably X is —CN, and preferably Z is H.
Preferably Y is selected from the following:
In a second aspect, the invention provides thienopyran compound having the formula I, II or III
wherein
X is H or an electron-withdrawing group selected from —CN, halogenated alkyl (preferably of 1-4 C atoms), oxophosphorus or oxosulphur groups (preferably —SO
2
R
1
or PO(OR
2
)
n
where R
1
is substituted or unsubstituted phenyl, pyridyl or thienyl and each R
2
is H or alkyl of 1-4 C atoms), oxocarbon groups (e.g. —CHO, —CONR
3
2
, —COOR
3
, wherein each R
3
is H or alkyl of 1-4 C atoms), —CH═NOH and
 and
A is
wherein B is a saturated or unsaturated carbon chain of 2-4 C atoms of which each carbon atom is unsubstituted or substituted by alkyl (preferably of 1-4 C atoms), halogen or hydroxy, or is a member of an epoxy ring.
Preferably X is —CN, and preferably A is selected from the following:
In a third aspect, the invention provides a thienopyran compound having the formula I, II or III
wherein
X is selected from oxophosphorus and oxosulphur groups (preferably —SO
2
R
1
or PO(OR
2
)
n
where R
1
is substituted or unsubstituted phenyl, pyridyl or thienyl and each R
2
is H or alkyl of 1-4 C atoms), and
D is
wherein B is a saturated or unsaturated carbon chain of 2-4 C atoms of which each carbon atom is unsubstituted or substituted by alkyl (preferably of 1-4 C atoms), halogen or hydroxy, or is a member of an epoxy ring.
Preferably X is —SO
2
(C
6
H
5
), and preferably D is
In all three of the above aspects of the invention, the preferred compounds are those having the formula I.
The invention also provides a pharmaceutical preparation comprising a thienopyran compound of the first three aspects above.
Further the invention provides a composition for administration to a human or other mammal, comprising as active ingredient a thienopyran compound of the first three aspects above, particularly a composition effective for hair growth modulation in a human or other mammal.
The results in the K
+
-stimulated isolated rat aorta test given below indicate that the compounds of the invention are potentially useful as anti-hypertensive agents to reduce blood pressure in mammals and also to reduce the immunological response associated with asthma.
As discussed below, it has been found that thienopyran compounds herein described have indications for activity for modulation of mammalian hair growth. Accordingly in another aspect the present invention consists in use of certain thienopyran compounds for hair growth modulation, including known compounds proposed for other purposes as described above. Particularly the invention provides cosmetic hair growth modulation, but hair growth modulation for non-cosmetic purposes is not excluded. In this aspect the invention provides a method of modulation of hair growth in a human or other mammal, comprising topical application of a thienopyran compound (including partially saturated thienopyran compounds, e.g. dihydro thienopyrans) which has activity of hair growth modulation in an amount effective to provide hair growth modulation.
More specifically in this aspect the invention provides 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 A
1
and A
2
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
−
), nitro, cyano and trifluoromethyl; acylamino (C
2-4
), alkoxy carbonyl (C
1-4
), CHO, COOH, CH═NOH, CONH
2
, 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
A
3
and A
4
are selected from hydro

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