SUBSTITUTED IMIDAZOPYRIMIDINES AND TRIAZOLOPYRIMIDINES

• US 20130040946A1
• Filed: 09/24/2012
• Published: 02/14/2013
• Est. Priority Date: 03/16/2007
• Status: Active Grant

• Current Assignee: Bayer Intellectual Property GmbH (Bayer AG)
• Original Assignee: Bayer Intellectual Property GmbH (Bayer AG)
• Inventors: Siegel, Stephan, Wilmen, Andreas, Rhrig, Susanne, Svenstrup, Niels, Gnoth, Mark Jean, Heitmeier, Stefan, Rester, Ulrich, Zubov, Dmitry, Strayle, Jochen, Sperzel, Michael
• Granted Patent: US 9,051,323 B2
• Time in Patent Office: Days
• US Class Current: 514/233.2
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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 25/20 Hypnotics; Sedatives
• 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 27/06 : Antiglaucoma agents or miotics
• 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 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/08 : for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/14 : for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The invention relates to substituted imidazo- and triazolopyrimidines and processes for their preparation, and their use for the manufacture of medicaments for the treatment and/or prophylaxis of diseases, in particular of haematological disorders, preferably of leucopenias and neutropenias.

Claims

1. Compound of the formula

2. The compound according to claim 1, characterized in that

A is N,

R¹ is hydrogen, trifluoromethyl, cyano, C₁-C₄-alkyl, C₁-C₆-alkylaminocarbonyl, dihydroxypropylaminocarbonyl, dihydroxybutylaminocarbonyl, dihydroxypentylaminocarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl, piperazinylcarbonyl, —

CH₂R¹³ or —

CH₂CH₂R¹⁴,

where alkylaminocarbonyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxy, amino, hydroxycarbonyl, aminocarbonyl, C₁-C₄-alkoxy, C₁-C₄-alkylamino, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl,

in which pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, oxo, C₁-C₄-alkyl, C₁-C₄-alkoxy and C₁-C₄-alkylamino,

and

where pyrrolidinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl and piperazinyl-carbonyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, oxo, C₁-C₄-alkyl, C₁-C₄-alkoxy and C₁-C₄-alkylamino,

and

where

R¹³ is hydroxycarbonyl, C₁-C₄-alkoxy, C₁-C₄-alkylamino, C₁-C₄-alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, imidazolyl, triazolyl or pyridyl,

in which alkoxy, alkylamino and alkylaminocarbonyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxy, amino, hydroxycarbonyl, aminocarbonyl, C₁-C₄-alkoxy, C₁-C₄-alkylamino, C₁-C₄-alkoxycarbonyl, C₁-C₄-alkylaminocarbonyl and C₁-C₄-alkylcarbonylamino,

and

in which pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, imidazolyl, triazolyl and pyridyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, oxo, C₁-C₄-alkyl, C₁-C₄-alkoxy and C₁-C₄-alkylamino,

and

where

R¹⁴ is hydroxycarbonyl, C₁-C₄-alkoxy, C₁-C₄-alkylamino, C₁-C₄-alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, imidazolyl, triazolyl or pyridyl,

in which alkoxy, alkylamino and alkylaminocarbonyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxy, amino, hydroxycarbonyl, aminocarbonyl, C₁-C₄-alkoxy, C₁-C₄-alkylamino, C₁-C₄-alkoxycarbonyl, C₁-C₄-alkylaminocarbonyl and C₁-C₄-alkylcarbonylamino,

and

in which pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, imidazolyl, triazolyl and pyridyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, oxo, C₁-C₄-alkyl, C₁-C₄-alkoxy and C₁-C₄-alkylamino,

R² is phenyl,

where phenyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkoxymethyl, C₁-C₄-alkylaminomethyl, C₁-C₄-alkylcarbonyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-alkylaminocarbonyl, C₁-C₄-alkylcarbonylamino, C₁-C₄-alkylsulphonyl, C₁-C₄-alkylsulphonylamino, C₁-C₄-alkylaminosulphonyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl and piperazinylmethyl,

in which phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl and piperazinylmethyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy and C₁-C₄-alkyl,

R⁴ is hydrogen or chlorine,

R¹⁶ is a group of the formula

3. The compound according to claim 1, wherein

A is N,

R¹ is hydrogen, methyl or —

CH₂R¹³,

where

R¹³ is morpholinyl,

R² is phenyl,

where phenyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of chlorine, fluorine, trifluoromethyl, trifluoromethoxy and methyl,

R⁴ is hydrogen,

R¹⁶ is a group of the formula

4. A method for preparing a compound of the formula (I) or one of its salts, its solvates or solvates of its salts according to claim 1, comprising reacting

[A] a compound of the formula

5. A pharmaceutical composition comprising a compound according to claim 1 in combination with an inert, non-toxic, pharmaceutically suitable excipient.

6. A method for controlling haematological disorders in humans and animals comprising administering a therapeutically acceptable amount of at least one compound according to claim 1.

7. A method for ex vivo expansion of adult haematopoietic stem cells from bone marrow, from peripheral blood or umbilical cord blood, comprising contacting the cells with an effective amount of a compound according to claim 1.

8. A method for controlling haematological disorders in humans and animals comprising administering a therapeutically acceptable amount of a pharmaceutical composition according to claim 5.