NEW PYRIDONE DERIVATES WITH MCH ANTAGONISTIC ACTIVITY AND MEDICAMENTS COMPRISING THESE COMPOUNDS

• US 20120010185A1
• Filed: 09/22/2011
• Published: 01/12/2012
• Est. Priority Date: 08/25/2006
• Status: Abandoned Application

• 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: MUELLER, Stephan Georg, ROTH, Gerald Juergen, KLEY, Joerg, RUDOLF, Klaus, LOTZ, Ralf, LEHMANN-LINTZ, Thorsten, STENKAMP, Dirk, HECKEL, Armin, SCHINDLER, Marcus
• Application Number:
  US13/239,537
• Publication Number:
  US 20120010185A1
• Time in Patent Office: Days
• US Class Current: 514/210.2
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• 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 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• 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 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• 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 9/10 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 213/63 : One oxygen atom
• CPC Class Codes: C07D 213/69 : Two or more oxygen atoms
• CPC Class Codes: C07D 213/74 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 237/14 : Oxygen atoms
• CPC Class Codes: C07D 237/16 : Two oxygen atoms
• CPC Class Codes: C07D 239/52 : Two oxygen atoms
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 451/06 : Oxygen atoms
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

The present invention relates to compounds of general formula I

wherein the groups and radicals B, k, L, U, V, W, X, Y, Z, R¹, R², have the meanings given in claim 1. Moreover the invention relates to pharmaceutical compositions containing at least one compound according to the invention. By virtue of their MCH-receptor antagonistic activity the pharmaceutical compositions according to the invention are suitable for the treatment of metabolic disorders and/or eating disorders, particularly obesity, bulimia, anorexia, hyperphagia and diabetes.

Claims

1. A compound of formula I

2. The compound according to claim 1, characterised in that the groups R¹, R² are selected independently of one another from the group comprising H, C_1-6-alkyl, C_3-5-alkenyl, C_3-5-alkynyl, C_3-7-cycloalkyl, hydroxy-C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-3-alkyl, (hydroxy-C_3-7-cycloalkyl)-C_1-3-alkyl, hydroxy-C_2-4-alkyl, ω

-NC—

C_2-3-alkyl, C_1-4-alkoxy, C_2-4-alkyl, hydroxy-C_1-4-alkoxy-C_2-4-alkyl, C_1-4-alkoxy-carbonyl-C_1-4-alkyl, carboxyl-C_1-4-alkyl, amino-C_2-4-alkyl, C_1-4-alkyl-amino-C_2-4-alkyl, di-(C_1-4-alkyl)amino-C_2-4-alkyl, cyclo-C_3-6-alkyleneimino-C_2-4-alkyl, pyrrolidin-3-yl, N—

(C_1-4-alkyl)-pyrrolidin-3-yl, pyrrolidinyl-C_1-3-alkyl, N—

(C_1-4-alkyl)-pyrrolidinyl-C_1-3-alkyl, piperidin-3-yl, piperidin-4-yl, N—

(C_1-4-alkyl)-piperidin-3-yl, N—

(C_1-4-alkyl) -piperidin-4-yl, piperidinyl-C_1-3-alkyl, N—

(C_1-4-alkyl)-piperidinyl-C_1-3-alkyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, phenyl-C_1-3-alkyl or pyridyl-C_1-3-alkyl, while in the above-mentioned groups and radicals one or more C atoms independently of one another may be mono- or polysubstituted by F, C_1-3-alkyl or hydroxy-C_1-3-alkyl, and/or one or two C atoms independently of one another may be monosubstituted by Cl, Br, OH, CF₃ or CN, and the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or different radicals R²⁰, in the case of a phenyl group may also additionally be monosubstituted by nitro, and/or one or more NH groups may be substituted by R²¹, wherein R²⁰ and R²¹ are defined as in claim 1.

3. The compound according to claim 1, characterised in that R¹ and R² together with the N atom to which they are bound form a heterocyclic group which is selected from the meanings azetidine, pyrrolidine, piperidine, azepan, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydro-pyridine, 2,3,4,7-tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-1H-azepine, piperazine in which the free imine function is substituted by R¹³, piperidin-4-one, morpholine, thiomorpholine, 1-oxo-thiomorpholin-4-yl and 1,1-dioxo-thiomorpholin-4-yl;

while one or more H atoms may be replaced by identical or different groups R¹⁴, and/or

the heterocyclic groups specified may be substituted by one or two identical or different carbo- or heterocyclic groups Cy in such a way that the bond between the alkylene bridge and the group Cy is made

via a single or double bond,

via a common C atom forming a spirocyclic ring system,

via two common adjacent C and/or N atoms forming a fused bicyclic ring system or

via three or more C and/or N atoms forming a bridged ring system;

and the groups R¹³, R¹⁴ and the group Cy are defined as in claim 1.

4. The compound according to claim 1, characterised in that R² denotes a C_1-3-alkylene bridge which is linked to the group Y, wherein the alkylene bridge may be substituted with one or more C_1-3-alkyl-groups, and R¹ is defined as in claim 2 or denotes a group selected from C_1-4-alkyl-CO—

, C_1-4-alkyl-O—

CO—

, (C_1-4-alkyl)NH—

CO—

or (C_1-4-alkyl)₂N—

CO—

wherein alkyl-groups may be mono- or polyfluorinated.

5. The compound according to claim 1, characterised in that X denotes a —

CH₂—

, —

CH₂—

CH₂—

or —

CH₂—

CH₂—

CH₂—

bridging group, wherein one or two hydrogen atoms may be replaced by identical or different C_1-3-alkyl-groups, while two alkyl-groups may linked together to form a 3 to 6-membered cycloalkyl group.

6. The compound according to claim 1, characterised in that the group Y denotes phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thiophenyl and thiazolyl all of which may be mono- or polysubstituted by identical or different substituents R²⁰, while R²⁰.

7. The compound according to claim 1, characterised in that the group Z denotes a group selected from —

CH₂—

CH₂—

, —

C(═

O)—

CH₂—

, —

C(═

CH₂)—

CH₂—

, —

C(OH)H—

CH₂— and

—

CFH—

CH₂—

.

8. The Compound according to claim 1, characterised in that the group W denotes —

CH₂—

O—

, —

O—

CH₂—

or —

NR^N—

CH₂—

.

9. The compound according to claim 1, characterised in that the group B is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thiophenyl and thiazolyl, wherein said group B may be mono- or polysubstituted by identical or different substituents R²⁰.

10. The physiologically acceptable salt of the compound according to claim 1.

11. A pharmaceutical composition comprising a compound according to claim 1 or its salt, together with one or more inert carriers or diluents.

12. A method for influencing the eating behaviour of a mammal which comprises administering to the mammal at least one compound according to claim 1 or its salt.

13. A method for reducing the body weight of a mammal which comprises administering to the mammal at least one compound according to claim 1 or its salt.

14. A method for preventing and/or treating symptoms and/or diseases which are caused by MCH or are otherwise causally connected with MCH in a mammal which comprises administering to the mammal at least one compound according to claim 1 or its salt.

15. A method for preventing and/or treating metabolic disorders and/or eating disorders, particularly obesity, bulimia, bulimia nervosa, cachexia, anorexia, anorexia nervosa and hyperphagia in a mammal which comprises administering to the mammal at least one compound according to claim 1 or its salt.

16. A method for preventing and/or treating diseases and/or disorders associated with obesity, particularly diabetes, especially type II diabetes, complications of diabetes including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, particularly arteriosclerosis and high blood pressure, arthritis and gonitis in a mammal which comprises administering to the mammal at least one compound according to claim 1 or its salt.

17. A method for preventing and/or treating hyperlipidaemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depression, anxiety, sleep disorders, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders in a mammal which comprises administering to the mammal at least one compound according to claim 1 or its salt.

18. A method for preventing and/or treating micturition disorders, such as for example urinary incontinence, hyperactive urinary bladder, urgency, nycturia and enuresis in a mammal which comprises administering to the mammal at least one compound according to claim 1 or its salt.

19. A method for preventing and/or treating dependencies and/or withdrawal symptoms in a mammal which comprises administering to the mammal at least one compound according to claim 1 or its salt.

20. A pharmaceutical composition comprising

a first active substance which is a compound according to claim 1,

a second active substance which is a compound selected from the group consisting of active substances for the treatment of diabetes, active substances for the treatment of diabetic complications, active substances for the treatment of obesity, preferably other than MCH antagonists, active substances for the treatment of high blood pressure, active substances for the treatment of hyperlipidaemia, including arteriosclerosis, active substances for the treatment of arthritis, active substances for the treatment of anxiety states and active substances for the treatment of depression,

and one or more inert carriers or diluents.