7-amino-2-alkylthiopteridin-4-yl-amines for the treatment of chemokine-related diseases
Pteridine compounds of formula (I) processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in the treatment of inflammatory diseases such as psoriasis, rheumatoid arthritis, diseases in which angiogenesis is assocated with raised CXCR2 chemokine levels (diabetic retinopathy) and COPD. The compounds are ligands for chemokine receptors and medical indications mentioned in the description include: diseases of the respiratory tract (COPDD, asthma, bronchitis, rhinitis, fibroid lung, pneumonia, etc.), diseases of the bones and joints (arthritis, etc.), skin-diseases (psoriasis, etc), diseases of the gastrointestinal tract, diseases in other tissues and systemic disease (multipe sclerosis, atherosclerosis, AIDS, type 1 diabetes, leprosy, sepsis, etc.), allograft rejection, cancers, cystic fibrosis, stroke, burn wounds, skin ulcers, reproductive disease and more.
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
in which
R 1 represents a C 3 –C 7 carbocyclic, C 1 –C 8 alkyl, C 2 –C 6 alkenyl or C 2 –C 6 alkynyl group, each of groups being optionally substituted by one or more substituent groups independently selected from halogen atoms, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 or an aryl or heteroaryl group, both of which may be optionally substituted by one or more substituents independently selected from halogen atoms, cyano, nitro, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 , C 1 –C 6 alkyl or trifluoromethyl groups;
one of R 2 and R 3 is hydrogen and the other is C 1 –C 8 alkyl substituted by hydroxy and one or more methyl or ethyl groups,
R 4 represents hydrogen, C 1 –C 6 alkyl or a phenyl group the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 11 and —NR 12 R 13
R 5 and R 6 independently represent a hydrogen atom or a C 1 –C 6 alkyl or phenyl group the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 14 and —NR 15 R 16 , —CONR 15 R 16 , —NR 15 COR 16 , —SONR 15 R 16 , NR 15 SO 2 R 16 or
R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system optionally containing a further heteroatom selected from oxygen and nitrogen atoms, which ring system may be optionally substituted by one or more substituent groups independently selected from phenyl, —OR 14 , —COOR 14 , —NR 15 R 16 , —CONR 15 R 16 , —NR 15 COR 16 , —SONR 15 R 16 , NR 15 SO 2 R 16 or C 1 –C 6 alkyl, itself optionally substituted by one or more substituents independently selected from halogen atoms and —NR 15 R 16 and —OR 17 groups;
R 10 represents a hydrogen atom or a C 1 –C 6 -alkyl or a phenyl group, the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 17 and —NR 15 R 16 ; and
each of R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 independently represents a hydrogen atom or a C 1 –C 6 , alkyl, or a phenyl group.
2. A compound according to claim 1 , wherein R 1 represents an optionally substituted benzyl group.
3. A compound according to claim 1 , wherein R 4 is hydrogen.
4. A compound according to claim 1 selected from:
(2R)-2-[[7-amino-2-[[(2,3 -difluorophenyl)methyl]thio]-4-pteridinyl]amino]-1-propanol, 2-[[7-amino-2-[[(2,3-difluorophenyl)methyl]thio]-4-pteridinyl]amino]-1,3-propanediol, 2-[[7-Amino-2-[[(2,3-difluorophenyl)methyl]thio]-4-pteridinyl]amino]-2-methyl-1-propanol, (2R)-2-[[7-Amino-2-[[(2,3-difluorophenyl)methyl]thio]-4-pteridinyl]amino]-1-butanol, 2-[[7-Amino-2-[[(2,3-difluorophenyl)methyl]thio]-4-pteridinyl]amino]-2-methyl-1,3-propanediol, (2R)-2-[[7-amino-2-[(phenylmethyl)thio]-4-pteridinyl]amino]-1-propanol, (2R)-2-[[7-amino-2-[[(2-fluorophenyl)methyl]thio]-4-pteridinyl]amino]-1-propanol, (2R)-2-[[7-amino-2-[[(3-chloro-4-methoxyphenyl)methyl]thio]-4-pteridinyl]amino]-1-propanol, (2R)-2-[[7-amino-2-[[(3-chlorophenyl)methyl]thio]-4-pteridinyl]amino]-1-propanol, (2R)-2-[[7-amino-2-[[(5-methyl-2-furanyl)methyl]thio]-4-pteridinyl]amino]-1-propanol, (2R)-2-[[7-amino-2-[(2-thienylmethyl)thio]-4-pteridinyl]amino]-1-propanol, (2R)-2-[[7-amino-2-[[(2-fluoro-4-methoxyphenyl)methyl]thio]-4-pteridinyl]amino]-1-propanol, (2R)-2-[[7-amino-2-[[(3-chloro-2-fluorophenyl)methyl]thio]-4-pteridinyl]amino]-1-propanol, and their pharmaceutically acceptable salts.
5. A process for the preparation of a compound of formula (I) as defined in claim 1 which comprises:
(a) treating a compound of formula (II):
wherein R 1 is defined as in formula (I) with an amine R 2 R 3 NH and optionally thereafter forming a pharmaceutically acceptable salt.
6. A compound of formula (II)
where R 1 represents a C 3 –C 7 carbocyclic, C 1 –C 8 alkyl, C 2 –C 6 alkenyl or C 2 –C 6 alkynyl group, each of the groups being optionally substituted by one or more substituent groups independently selected from halogen atoms, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 or an aryl or heteroaryl group, both of which may be optionally substituted by one or more substituents independently selected from halogen atoms, cyano, nitro, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 , C 1 –C 6 alkyl or trifluoromethyl groups
R 4 represents hydrogen, C 1 –C 6 alkyl or a phenyl group the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 11 and —NR 12 R 13
R 5 and R 6 independently represent a hydrogen atom or a C 1 –C 6 alkyl or phenyl group the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 14 and —NR 15 R 16 , —CONR 15 R 16 , —NR 15 COR 16 , —SONR 15 R 16 , NR 15 SO 2 R 16 or
R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system optionally containing a further heteroatom selected from oxygen and nitrogen atoms, which ring system may be optionally substituted by one or more substituent groups independently selected from phenyl, —OR 4 , —COOR 14 , —NR 15 R 16 , —CONR 15 R 16 , —NR 15 COR 16 , —SONR 15 R 16 , NR 15 SO 2 R 16 or C 1 –C 6 alkyl, itself optionally substituted by one or more substituents independently selected from halogen atoms and —NR 15 R 16 and —OR 17 groups;
R 10 represents a hydrogen atom or a C 1 –C 6 -alkyl or a phenyl group, the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 17 and —NR 15 R 16 ; and
each of R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 independently represents a hydrogen atom or a C 1 –C 6 , alkyl, or a phenyl group.
7. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
8. A process for the preparation of a pharmaceutical composition as claimed in claim 7 which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 with a pharmaceutically acceptable adjuvant, diluent or carrier.
9. A process for the preparation of a pharmaceutical composition comprising mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , with a pharmaceutically acceptable adjuvant, diluent or carrier.