Beta-hydroxy heterocyclic amines and their use in the treatment of hyperglycaemia
There is herein provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X, R 1 , ring A, m and n have meanings as provided in the description.
1. A compound of formula IF:
or a pharmaceutically acceptable salt thereof, wherein:
z represents 0, 1 or 2;
when z represents 0 then m represents 0 to 5, or when z represents 1 then m represents 1 to 7 or when z represents 2 then m represents 0 to 9;
each R 1 independently represents C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl each 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 e , 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 e 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, C 2-3 alkynyl, and ═O,
wherein the C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl each are optionally substituted by one or more halo;
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, C 2-3 alkynyl, and ═O, wherein the C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl each are optionally substituted by one or more halo;
n represents 0 to 5;
each p independently represents 0, 1 or 2; and
each q independently represents 1 or 2,
provided that the compound is not rel-(1R)-((2S)-4-methylpyrrolidin-2-yl)(phenyl)methanol.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 represents C 1-6 alkyl optionally substituted by one or more F.
3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, 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 R b , R c and R d each independently represent H or C 1-4 alkyl optionally substituted by one or more F.
4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein n represents 0, 1, 2 or 3.
5. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein each X independently represents F, Cl, —NH 2 , —CF 3 or —OH.
6. The compound according to claim 1 , wherein the compound is a compound of formula IH:
or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein z represents 1 or 2.
8. A pharmaceutical composition comprising a compound, and optionally one or more pharmaceutically acceptable adjuvant, diluent and/or carrier, wherein the compound is a compound of formula IF:
or a pharmaceutically acceptable salt thereof, wherein:
z represents 0, 1 or 2;
when z represents 0 then m represents 0 to 5, or when z represents 1 then m represents 1 to 7 or when z represents 2 then m represents 0 to 9;
each R 1 independently represents C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl each 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 e , 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 e 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, C 2-3 alkynyl, and ═O, wherein the C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl each are optionally substituted by one or more halo;
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, C 2-3 alkynyl, and ═O, wherein the C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl each are optionally substituted by one or more halo;
n represents 0 to 5;
each p independently represents 0, 1 or 2; and
each q independently represents 1 or 2.
9. 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, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula IF:
or a pharmaceutically acceptable salt thereof, wherein:
z represents 0, 1 or 2;
when z represents 0 then m represents 0 to 5, or when z represents 1 then m represents 0 to 7 or when z represents 2 then m represents 0 to 9;
each R 1 independently represents C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl each 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 e , 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 e and/or R 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, C 2-3 alkynyl, and ═O, wherein the C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl each are optionally substituted by one or more halo;
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, C 2-3 alkynyl, and ═O, wherein the C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl each are optionally substituted by one or more halo;
n represents 0 to 5;
each p independently represents 0, 1 or 2; and
each q independently represents 1 or 2.
10. The method according to claim 9 , wherein the hyperglycaemia or disorder characterized by hyperglycaemia is type 2 diabetes.
11. The method according to claim 9 , wherein the patient displays severe insulin resistance.
12. The method according to claim 9 , wherein the disorder characterised by hyperglycaemia is selected from the group consisting of Rabson-Mendenhall syndrome, Donohue's syndrome, Type A and Type B syndromes of insulin resistance, the HAIR-AN syndromes, pseudoacromegaly, and lipodystrophy.
13. A combination product comprising:
(a) a compound; 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; and
wherein the compound is a compound of formula IF:
or a pharmaceutically acceptable salt thereof, wherein:
z represents 0, 1 or 2;
when z represents 0 then m represents 0 to 5, or when z represents 1 then m represents 0 to 7 or when z represents 2 then m represents 0 to 9;
each R 1 independently represents C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl each optionally substituted b 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 e , 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 e 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, C 2-3 alkynyl, and ═O, wherein the C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl each are optionally substituted by one or more halo;
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, C 2-3 alkynyl, and ═O, wherein the C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl each are optionally substituted by one or more halo;
n represents 0 to 5;
each p independently represents 0, 1 or 2; and
each q independently represents 1 or 2.
14. 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, wherein the compound is a compound of formula IF:
or a pharmaceutically acceptable salt thereof, wherein:
z represents 0, 1 or 2;
when z represents 0 then m represents 0 to 5, or when z represents 1 then m represents 0 to 7 or when z represents 2 then m represents 0 to 9;
each R 1 independently represents C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl each 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 e , 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 e 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, C 2-3 alkynyl, and ═O, wherein the C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl each are optionally substituted by one or more halo;
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 e1 , 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, C 2-3 alkynyl, and ═O, wherein the C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl each are optionally substituted by one or more halo;
n represents 0 to 5;
each p independently represents 0, 1 or 2; and
each q independently represents 1 or 2.
15. A process for the preparation of a compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof, comprising the step of:
deprotection of a compound of the following formula:
wherein n, m, X and R 1 are as defined in claim 1 , wherein ring A is
wherein z is as defined in claim 1 , and wherein PG 4 represents a suitable protecting group.
16. The compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein:
X 1 and X 5 each represent H, F or Cl; 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, R b , R c and R d each independently represent H or C 1-4 alkyl optionally substituted by one or more F.