Granted Patent B2

US 12,280,023 · App. 18/133,060 · Granted Apr 22, 2025

Inventors: Benjamin Pelcman (Stockholm, SE); Tore Bengtsson (Vaxholm, SE)

Assignee: ATROGI AB

A61K31/137A61K31/167A61P3/10C07C215/34C07C215/42C07C215/68C07C233/43

Abstract

Claims (92)

1. A compound of formula IB

or a pharmaceutically acceptable salt thereof, wherein:

R 1 represents C 4-12 alkyl optionally substituted by one or more halo;

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

or R 2 and R 3 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;

X represents Cl, Br, 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 optionally substituted by one or more groups independently selected from G;

each R b , R c , R d , R e , R f and R independently represents H or C 1-6 alkyl 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 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 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 optionally substituted by one or more halo, and ═O;

m represents 2;

n represents 1;

each p independently represents 0, 1 or 2; and

each q independently represents 1 or 2,

wherein alkyl groups may be straight-chain or, when there is a sufficient number of carbon atoms, be branched-chain, and/or cyclic or part cyclic.

2. The compound according to claim 1 , wherein R 1 represents C 4-10 alkyl optionally substituted by one or more halo.

3. The compound according to claim 1 , wherein R 1 represents n-butyl, tert-butyl or 1-methyl butyl.

4. The compound according to claim 1 , wherein R 2 represents H and R 3 represents H or methyl.

5. The compound according to claim 1 , wherein R 2 and R 3 each represent H.

6. The compound according to claim 1 , wherein and the F atoms are located in the 2- and 3-positions, or the 3- and 4-positions, or the 3- and 5-positions.

7. The compound according to claim 1 , wherein:

X represents Cl, Br, 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 or ═O.

8. The compound according to claim 1 , wherein X represents Cl, Br, R a , —N(R b )R c or —OH, wherein R a represents C 1-2 alkyl optionally substituted by 1 or more F, and R b and R c each independently represent H or C 1-4 alkyl optionally substituted by ═O.

9. The compound according to claim 1 , wherein X represents Cl, —NH 2 , —NHC(O)CH 3 , —CF 3 or —OH.

10. The compound according to claim 1 , wherein X represents Cl, R a , —NH 2 , —NHC(O)CH 3 or —OH, wherein R a represents C 1-2 alkyl optionally substituted by one or more F.

11. The compound according to claim 1 , wherein X represents —NH 2 , —NHC(O)CH 3 or —OH.

12. The compound according to claim 1 , wherein X is located in the 3-, 4- or 5-position.

13. The compound according to claim 1 , wherein the compound is a compound of formula IC

wherein

Y 1 and Y 5 each independently represent H or F; and

Y 2 , Y 3 and Y 4 each independently represent H, F, R a , —CN, —N(R b )R c , or —OH, wherein R a represents C 1-2 alkyl optionally substituted by one or more F, and R b and R c each independently represent H or C 1-4 alkyl optionally substituted by ═O,

with the proviso that two of Y 1 to Y 5 represent F.

14. The compound according to claim 13 , wherein:

Y 1 and Y 5 each independently represent H or F; and

Y 2 , Y 3 and Y 4 each independently represent H, F, —N(R b ) R c , —CN or —OH, wherein R b and R c each independently represent H or C 1-4 alkyl optionally substituted by ═O,

with the proviso that two of Y 2 , Y 3 and Y 4 represent F.

15. The compound according to claim 1 , wherein the compound is

(R)-1-(3-amino-2,4-difluorophenyl)-2-(tert-butylamino) ethan-1-ol;

or a pharmaceutically acceptable salts thereof.

16. The compound according to claim 13 , wherein:

Y 1 and Y 5 each independently represent H or F; and

Y 2 , Y 3 and Y 4 each independently represent H, F, —NH 2 , —NHC(O)CH 3 or —OH, with the proviso that two of Y 2 , Y 3 and Y 4 represent F.

17. A pharmaceutical composition comprising a compound of Formula (IB)

or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable adjuvant, diluent and/or carrier,

wherein:

R 1 represents C 4-12 alkyl optionally substituted by one or more halo;

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

or R 2 and R 3 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 Cl, Br, 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 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 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 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 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 optionally substituted by one or more halo, and ═O;

m represents 2;

n represents 0 to 4;

each p independently represents 0, 1 or 2; and

each q independently represents 1 or 2,

wherein alkyl groups may be straight-chain or, when there is a sufficient number of carbon atoms, be branched-chain, and/or cyclic or part cyclic.

18. A method of treating hyperglycemia or a disorder characterized by hyperglycemia 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, or a pharmaceutical composition according to claim 17 .

19. The method according to claim 18 , wherein the treatment is of type 2 diabetes.

20. The method according to claim 18 , wherein the hyperglycaemia or disorder characterized by hyperglycemia is characterized by, the patient displaying severe insulin resistance.

21. The method according to claim 18 , wherein the disorder characterized by hyperglycemia 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.

22. A combination product comprising:

(a) a compound as defined in claim 1 or a pharmaceutical composition as defined in claim 17 ; and

(b) one or more other therapeutic agent that is useful in the treatment of hyperglycemia 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.

23. A kit-of-parts comprising:

(a) a pharmaceutical composition as defined in claim 17 , and

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

24. 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 X 1 , X 2 , X 3 , X 4 , R 2 and R 3 are as defined in claim 1 , with a compound of formula III

H 2 N—R 1   (III)

wherein R 1 is as defined in claim 1 , optionally in the presence of a suitable solvent;

(iia) reaction of a compound of formula IV

wherein m, n, X, R 1 , R 2 and R 3 are as defined in claim 1 and Y 1 represents H or PG 1 wherein PG 1 is a suitable protecting group, with a suitable reduction agent;

(iib) reaction of a compound of formula IV but wherein Y 1 represents PG 1 wherein PG 1 is a suitable protecting group in the presence of a suitable catalyst 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 m, n, R 1 , R 2 and R 3 are as defined in claim 1 , Y 2 represents H or PG 2 , wherein PG 2 represents a suitable protecting group, and PG 3 represents a suitable protecting group, under suitable conditions;

(iv) for compounds wherein at least one X is present and represents NH 2 or NHC(O)CH 3 , deprotection of a compound of formula VI

wherein m, n, X, R 1 , R 2 and R 3 are as defined in claim 1 , Y 3 represents H or PG 5 , wherein PG 5 represents a suitable protecting group, Y 4 represents H, —C(O)CH 3 or PG 6 , wherein PG 6 represents a suitable protecting group, and PG 4 represents a suitable protecting group, under suitable conditions; or

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

wherein m, n, X, R 1 , R 2 and R 3 are as defined in claim 1 , under suitable conditions.

25. The compound according to claim 1 , wherein the compound is present at a purity of at least 80% relative to other stereoisomers.

26. The compound according to claim 1 , wherein the compound is present in an enantiomeric excess (e.e.) of at least 90%.

27. The pharmaceutical composition according to claim 17 , wherein the compound is present at a purity of at least 80% relative to other stereoisomers.

28. The pharmaceutical composition according to claim 17 , wherein the compound is present in an enantiomeric excess (e.e.) of at least 90%.

Assignments (1)

Priority Claims (1)

Continuity (2)

References Cited (400)