Substituted pteridines for the treatment of inflammatory diseases

• US 20060116371A1
• Filed: 11/18/2005
• Published: 06/01/2006
• Est. Priority Date: 11/29/2004
• Status: Active Grant

• Current Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Dollinger, Horst, Jung, Birgit, Martyres, Domnic, Nickolaus, Peter
• Granted Patent: US 7,718,654 B2
• Time in Patent Office: Days
• US Class Current: 514/227.800
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/10 Expectorants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 475/06 : with a nitrogen atom directly attached in position 4
• CPC Class Codes: C07D 475/08 : with a nitrogen atom directly attached in position 2

Abstract

The invention relates to new pteridines which are suitable for the treatment of respiratory or gastrointestinal complaints or diseases, inflammatory diseases of the joints, skin or eyes, diseases of the peripheral or central nervous system or cancers, as well as pharmaceutical compositions which contain these compounds.

Claims

1. A compound of the formula 1

2. A compound of the formula 1, according to claim 1, wherein

R³ denotes aryl, het, hetaryl or a group of formula 1a,

wherein

A denotes aryl, hetaryl;

X denotes NR^3.2, S, O;

Y denotes C_1-4-alkylene, optionally substituted by one or more R^3.3

m denotes 0, 1, 2;

R^3.1 each independently of one another denote C_1-6-alkyl, C_1-6-haloalkyl, C_1-6-alkyl-CONH₂, —

C_1-6-alkyl-NH₂, O—

C_1-6-alkyl, O—

C_1-6-haloalkyl, NHCO—

C_1-6-alkyl, SO₂—

C_1-6alkyl, aryl, halogen, CN, OH, CONH₂;

or

R^3.1 together with two atoms of A forms a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring which may contain one or more oxygen or nitrogen atoms;

R^3.2 denotes H, C_1-6-alkyl;

R^3.3 each independently of one another denote C_1-6-alkyl, C_1-6-alkyl-OH, C_3-6-cycloalkyl-OH, COO—

C_1-1-alkyl, COOH, CONH₂;

or

R^3.3 together with one or two carbon atoms of Y forms a carbocyclic ring with 3, 5 or 6 carbon atoms

R⁴ denotes a group selected from among C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C_3-6-cycloalkyl, C_3-6-cycloalkenyl, O—

C_1-6-alkyl, S—

C_1-6-alkyl, C_1-6-haloalkyl, NR^4.1R^4.2 or a group selected from among aryl, het and hetaryl, optionally substituted by one or more groups selected from among C_1-6-alkyl, C_1-6-haloalkyl, CN, O—

C_1-6-alkyl, halogen,

R^4.1 denotes H, C₁-alkyl;

R^4.2 denotes C_1-6-alkyl, aryl;

or a pharmacologically acceptable salt thereof.

3. A compound of the formula 1 according to claim 1, wherein

R⁴ denotes C_3-6-cycloalkyl;

or a pharmacologically acceptable salt thereof.

4. A compound of the formula 1 according to claim 1, wherein

R³ denotes a group of formula 1a,

wherein

A denotes aryl, hetaryl;

X denotes NH, S, O;

Y denotes C_1-4-alkylene, optionally substituted by one or more R^3.3

m denotes 0, 1, 2;

R^3.1 each independently of one another denote C_1-4-alkyl, C_1-4-haloalkyl, C_1-4-alkyl-CONH₂, C_1-4-alkyl-NH₂, O—

C_1-4-alkyl, O—

C_1-4-haloalkyl, NHCO—

C_1-4-alkyl, SO₂—

C_1-4-alkyl, halogen, CN, OH, CONH₂;

R^3.3 each independently of one another denote C_1-4-alkyl, C_1-4-alkyl-OH, C_3-4-cycloalkyl-OH, COO—

C_1-4-alkyl, COOH, CONH₂;

or

R^3.3 together with one or two carbon atoms of Y forms a carbocyclic ring with 3, 5 or 6 carbon atoms

or a pharmacologically acceptable salt thereof.

5. A compound of the formula 1 according to claim 1, wherein

R³ denotes a group of formula 1a,

wherein

A denotes aryl, hetaryl;

x denotes NH, S, O;

Y denotes C_1-4-alkylene, optionally substituted by one or two R^3.3

m denotes 0, 1, 2;

R^3.1 each independently of one another denote C_1-4-alkyl, C_1-4-haloalkyl, O—

C_1-4-alkyl, O—

C_1-4-haloalkyl, halogen, CN, OH;

R^3.3 each independently of one another denote C_1-4-alkyl, COOH, CONH₂;

or

R^3.3 together with one or two carbon atoms of Y forms a carbocyclic ring with 3 carbon atoms

or a pharmacologically acceptable salt thereof.

6. A compounds of the formula 1 according to claim 1, wherein

R² denotes halogen, NR^2.1R^2.2, het, optionally substituted by a group selected from among C_3-4-cycloalkyl, C_7-11-aralkyl and NMe₂;

R^2.1 denotes C_7-11-aralkyl;

R^2.2 denotes H;

R³ denotes NR^3.1R^3.2, SR^3.1 or het;

R^3.1 denotes C₁-alkylene-C_3-4-cycloalkyl or C_7-11-aralkyl, optionally substituted by a group selected from the group halogen;

R^3.2 denotes H;

R⁴ denotes a group selected from among C_1-6alkyl, C_3-6-cycloalkyl, O—

C_1-6alkyl, C_1-6-haloalkyl, NR^4.1R^4.2 or a group selected from among aryl, het and hetaryl, optionally substituted by one or more groups selected from among C_1-6alkyl, C_1-6-haloalkyl, CN, O—

C_1-6alkyl, halogen,

R^4.1 denotes H, C_1-6alkyl;

R^4.2 denotes C_1-6-alkyl, aryl;

or a pharmacologically acceptable salt thereof.

7. A compound of the formula 1 according to claim 1, wherein

R² denotes halogen, NH(benzyl), het, optionally substituted by a group selected from among cyclopropyl, benzyl and NMe₂;

R³ denotes NR^3.1R^3.2, SR^3.1 or het;

R^3.1 denotes methylcyclohexyl or benzyl, optionally substituted by a group selected from among fluorine and chlorine;

R^3.2 denotes H;

R⁴ denotes a group selected from among methyl, ethyl, propyl, 2-methylpropyl, cyclopropyl, cyclohexyl, methoxy, CF₃, NR^4.1R^4.2, het, hetaryl, aryl, optionally substituted by one or more groups selected from among methyl, CF₃, CN, methoxy, fluorine, chlorine,

R^4.1 denotes H, methyl, ethyl;

R^4.2 denotes methyl, ethyl, phenyl;

or a pharmacologically acceptable salt thereof.

8. A compound of the formula 1 according to claim 1, wherein

R¹ denotes a five- or six-membered heterocyclic ring which contains a nitrogen atom;

R² denotes chlorine, NH(benzyl), a six-membered heterocyclic ring which may contain one or more nitrogen atoms and is optionally substituted by a group selected from among cyclopropyl, benzyl and NMe₂;

R³ denotes NR^3.1R^3.2, SR^3.1 or a six-membered heterocyclic ring which may contain one or more heteroatoms selected from among nitrogen and oxygen;

R^3.1 denotes methylcyclohexyl or benzyl, optionally substituted by a group selected from among fluorine and chlorine;

R^3.2 denotes H;

R⁴ denotes a group selected from among methyl, ethyl, propyl, 2-methylpropyl, cyclopropyl, cyclohexyl, methoxy, CF₃, NR^4.1R^4.2,

aryl, optionally substituted by one or more groups selected from among methyl, CF₃, CN, methoxy, fluorine, chlorine,

a five- or six-membered heterocyclic ring which may contain one or more heteroatoms selected from among nitrogen and oxygen,

a five-membered heterocyclic aromatic group which may contain one or more groups selected from among nitrogen and oxygen,

an aromatic or non-aromatic bicyclic group which may contain one or more heteroatoms selected from among sulphur and oxygen;

R^4.1 denotes H, methyl, ethyl;

R^4.2 denotes methyl, ethyl, phenyl;

or a pharmacologically acceptable salt thereof.

9. A compound of the formula 1 according to claim 1, wherein

R¹ denotes a group selected from among

R² denotes a group selected from among chlorine,

R³ denotes a group selected from among

R⁴ denotes a group selected from among methyl, ethyl, propyl, 2-methylpropyl, methoxy, CF₃, NMe₂, NEt₂,

or a pharmacologically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

11. A method for treating a disease which can be treated by inhibiting the PDE4 enzyme which comprises administering a therapeutically effective amount of a compound of the formula 1 according to claim 1.

12. A method for treating respiratory or gastrointestinal complaints or diseases, and also inflammatory diseases of the joints, skin or eyes, cancers, as well as diseases of the peripheral or central nervous system which comprises administering a therapeutically effective amount of a compound of the formula 1 according to claim 1.

13. A method for treating respiratory or pulmonary diseases which are accompanied by increased mucus production, inflammation and/or obstructive diseases of the airways which comprises administering a therapeutically effective amount of a compound of the formula 1 according to claim 1.

14. A method for treating an inflammatory disease of the gastrointestinal tract which comprises administering a therapeutically effective amount of a compound of the formula 1 according to claim 1

15. A method for treating COPD, chronic sinusitis, asthma, Crohn'"'"'s disease or ulcerative colitis which comprises administering a therapeutically effective amount of a compound of the formula 1 according to claim 1.

16. A method for treating depression, bipolar or manic depression, acute and chronic anxiety states, schizophrenia, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, acute and chronic multiple sclerosis or acute and chronic pain as well as injuries to the brain caused by stroke, hypoxia or craniocerebral trauma which comprises administering a therapeutically effective amount of a compound of the formula 1 according to claim 1.

17. A method for treating acute lymphatic and acute myeloid leukaemia, chronic lymphatic and chronic myeloid leukaemia, osteosarcoma and gliomas which comprises administering a therapeutically effective amount of a compound of the formula 1 according to claim 1.