Chiral beta-hydroxyethylamines and their use in the treatment of hyperglycemia

1. A compound of formula I

or a pharmaceutically acceptable salt thereof, wherein:

R 1 represents C 3-11 alkyl, C 3-11 alkenyl, or C 3-11 alkynyl each optionally substituted by one or more halo;

R 2 represents C 1-2 alkyl, C 2 alkenyl, or C 2 alkynyl each optionally substituted by one or more halo;

R 3 and R 4 each independently represent H or C 1-3 alkyl, C 2-3 alkenyl, or C 2-3 alkynyl each optionally substituted by one or more halo;

or R 3 and R 4 may be linked together to form, together with the carbon atom to which they are attached, a 3- to 6-membered ring, which ring optionally is substituted by one or more groups independently selected from halo and C 1 alkyl optionally substituted by one or more halo;

each X independently represents halo, R a , —CN, —N 3 , —N(R b )R c , —NO 2 , —ONO 2 , —OR d , —S(O) p R e or —S(O) q N(R f )R g ;

R a represents C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl each optionally substituted by one or more groups independently selected from G;

each R b , R c , R d , R e , R f and R g independently represents H or C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl each optionally substituted by one or more groups independently selected from G;

or alternatively any of R b and R c and/or R f and R g may be linked together to form, together with the nitrogen atom to which they are attached, a 4- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl each optionally substituted by one or more halo, and ═O;

G represents halo, —CN, —N(R a1 )R b1 , OR c1 , —S(O) p R d1 , —S(O) q N(R e1 )R f1 or ═O;

each R a1 , R b1 , R c1 , R d1 , R e1 and R f1 independently represents H or C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl each optionally substituted by one or more halo;

or alternatively any of R a1 and R b1 and/or R e1 and R f1 may be linked together to form, together with the nitrogen atom to which they are attached, a 4- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl each optionally substituted by one or more halo, and ═O;

n represents 0 to 5;

each p independently represents 0, 1 or 2; and

each q independently represents 1 or 2;

wherein the compound of formula I is present in a diastereomeric excess of at least 90%.

2. The compound according to claim 1 , wherein R 1 represents C 3-6 alkyl optionally substituted by one or more F.

3. The compound according to claim 1 , wherein R 2 represents C 1-2 alkyl optionally substituted by one or more F.

4. The compound according to claim 1 , wherein R 1 represents n-propyl and R 2 represents methyl.

5. The compound according to claim 1 , wherein R 3 and R 4 each represent H.

6. The compound according to claim 1 , wherein:

each X independently represents halo, R a , —CN, —N 3 , —N(R b )R c , —NO 2 or OR d , wherein R a represents C 1-4 alkyl optionally substituted by one or more F, and wherein R b , R c and R d each independently represent H or C 1-4 alkyl optionally substituted by one or more F or ═O.

7. The compound according to claim 1 , wherein n represents 0, 1, 2 or 3.

8. The compound according to claim 1 , wherein the compound is a compound of formula IA

wherein:

X 1 , X 2 , X 3 , X 4 and X 5 each independently represent H or X.

9. The compound according to claim 8 , wherein:

X 1 and X 5 each represent H; and

X 2 , X 3 and X 4 each independently represent H, halo, R a , —CN, —N 3 , —N(R b )R c , —NO 2 or —OR d ;

wherein R a represents C 1-4 alkyl optionally substituted by one or more F, and wherein R b , R c

and R d each independently represent H or C 1-4 alkyl optionally substituted by one or more F or ═O.

10. The compound according to claim 8 , wherein the compound of formula I or formula IA is a compound of formula IC

11. The compound according to claim 10 , wherein:

X 1 , X 2 and X 5 each represent H;

X 3 and X 4 each independently represent H, F or —OH;

R 1 represents C 3 alkyl;

R 2 represents C 1 alkyl; and

R 3 and R 4 both represent H.

12. A pharmaceutical composition comprising a compound as defined in claim 1 , and optionally one or more pharmaceutically acceptable adjuvant, diluent and/or carrier.

13. A method of treating hyperglycaemia or a disorder characterized by hyperglycaemia comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof.

14. The method according to claim 13 , wherein the hyperglycaemia or disorder characterized by hyperglycaemia is type 2 diabetes.

15. The method according to claim 13 , wherein the patient displays severe insulin resistance.

16. The method according to claim 13 , wherein the disorder characterised by hyperglycaemia is selected from the group consisting of Rabson-Mendenhall syndrome, Donohue's syndrome (leprechaunism), Type A and Type B syndromes of insulin resistance, the HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans ) syndromes, pseudoacromegaly, and lipodystrophy.

17. A combination product comprising:

(a) a compound as defined in claim 1 ; and

(b) one or more other therapeutic agent that is useful in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia,

wherein each of components (a) and (b) is formulated in admixture, optionally with one or more a pharmaceutically-acceptable adjuvant, diluent or carrier.

18. A kit-of-parts comprising:

(a) a pharmaceutical composition comprising a compound as defined in claim 1 , and optionally one or more pharmaceutically acceptable adjuvant, diluent and/or carrier, and

(b) one or more other therapeutic agent that is useful in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia, optionally in admixture with one or more pharmaceutically-acceptable adjuvant, diluent or carrier,

which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.

19. A process for the preparation of a compound as defined in claim 1 , or

a pharmaceutically acceptable salt thereof, comprising the step of:

(i) reaction of a compound of formula II

wherein n, X, R 3 , R 4 and n are as defined in claim 1 , with a compound of formula III

wherein R 1 and R 2 are as defined in claim 1 , optionally in the presence of a suitable solvent known to those skilled in the art;

(iia) reaction of a compound of formula IV

wherein n, X, R 1 , R 2 , R 3 and R 4 are as defined in claim 1 and Y 1 represents H or PG 1 wherein PG 1 is a suitable protecting group as known to those skilled in the art with a suitable reduction agent as known to those skilled in the art;

(iib) for compounds of formula IC

wherein X 1 , X 2 , X 3 , X 4 and X 5 each independently represent H or X, wherein X, R 1 , R 2 , R 3 , and R 4 are as defined in claim 1 , reaction of a compound of formula IV as defined in step (iia) but wherein Y 1 represents PG 1 wherein PG 1 is a suitable protecting group as known to those skilled in the art in the presence of hydrogen or a suitable hydrogen donor and optionally in the presence of a base and in the presence of a suitable solvent;

(iii) for compounds wherein at least one X is present and represents —OH, deprotection of a compound of formula V

wherein n, R 1 , R 2 , R 3 and R 4 are as defined in claim 1 , Y 2 represents H or PG 2 , wherein PG 2 represents a suitable protecting group as known to those skilled in the art, and PG 3 represents a suitable protecting group as known to those skilled in the art under conditions known to those skilled in the art;

(iv) for compounds wherein at least one X is present and represents NH 2 , deprotection of a compound of formula VI

wherein n, X, R 1 , R 2 , R 3 and R 4 are as defined in claim 1 , Y 3 represents H or PG 5 , wherein PG 5 represents a suitable protecting group as known to those skilled in the art, Y 4 represents H or PG 6 , wherein PG 6 represents a suitable protecting group as known to those skilled in the art, and PG 4 represents a suitable protecting group as known to those skilled in the art, under conditions known to those skilled in the art;

(v) for compounds wherein at least one X is present and represents NH 2 , reduction of a compound of formula VII

wherein n, X, R 1 , R 2 , R 3 and R 4 are as defined in claim 1 , under conditions known to those skilled in the art.