Cyclobutyl amine derivatives

• US 20070078133A1
• Filed: 06/01/2006
• Published: 04/05/2007
• Est. Priority Date: 06/03/2005
• Status: Active Grant

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbott Laboratories Incorporated
• Inventors: Liu, Huaqing, Cowart, Marlon, Hancock, Kathryn, Hancock, Arthur
• Granted Patent: US 7,553,964 B2
• Time in Patent Office: Days
• US Class Current: 514/235.200
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• 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 25/08 Antiepileptics; Anticonvulsants
• 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 25/20 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 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 27/16 Otologicals
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 207/06 : with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 401/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 403/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 417/10 : linked by a carbon chain containing aromatic rings

Abstract

Compounds of formula (I) are useful in treating conditions or disorders prevented by or ameliorated by histamine-3 receptor ligands. Also disclosed are pharmaceutical compositions comprising the histamine-3 receptor ligands, methods for using such compounds and compositions, and a process for preparing compounds within the scope of formula (I).

Claims

1. A compound of formula:

2. The compound of claim 1, wherein R₁ is -L₂-R_6a-L₃-R_6b, wherein L₂ is a bond, R_6b is hydrogen, L₃ is a bond, and R_6a is selected from a 5- or 6-membered heteroaryl ring.

3. The compound of claim 2, wherein R_6a is an unsubstituted or substituted ring selected from the group consisting of furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, [1,2,3]thiadiazolyl, [1,2,4]thiadiazolonyl, [1,2,5]thiadiazolonyl, [1,3,4]thiadiazinonyl, [1,2,3]oxadiazolyl, [1,2,4]oxadiazolonyl, [1,2,5]oxadiazolonyl, [1,3,4]oxadiazinonyl, thiazolyl, thienyl, [1,2,3]triazinyl, [1,2,4]triazinyl, [1,3,5]triazinyl, [1,2,3]triazolyl, [1,2,4]triazolyl, pyridazinonyl, pyridonyl, and pyrimidinonyl.

4. The compound of claim 2, wherein R_6a is an unsubstituted or substituted ring selected from the group consisting of pyrimidinyl, pyridazinonyl, pyridinyl, and pyrazolyl.

5. The compound of claim 1, wherein R₁ is -L₂-R_6a-L₃-R_6b, wherein L₂ is a bond, R_6b is hydrogen, L₃ is a bond, and R_6a is selected from a 8- to 10-membered bicyclic heteroaryl ring.

6. The compound of claim 5, wherein R_6a is an unsubstituted or substituted ring selected from the group consisting of indolyl, benzothienyl, benzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzoisothiazolyl, benzoisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pteridinyl, purinyl, naphthyridinyl, cinnolinyl, thieno[2,3-d]imidazole, and pyrrolopyrimidinyl.

7. The compound of claim 6, wherein R_6a is unsubstituted or substituted benzothiazolyl.

8. The compound of claim 1, wherein one of R₃, R_3a, and R_3b is halogen and the others are hydrogen.

9. The compound of claim 1, wherein R₄ and R₅ taken together with the nitrogen atom to which each is attached form a 4- to 8-membered non-aromatic ring represented by formula (a).

10. The compound of claim 9, wherein at least one substituent represented by R₇, R₈, R₉, and R₁₀ is selected from the group consisting of alkyl, fluoroalkyl, and hydroxyalkyl or at least one substituent represented by R_x or R_y is alkyl, fluoro, or hydroxy.

11. The compound of claim 1, wherein R₄ and R₅ are taken together with the nitrogen atom to which each is attached to form a (2R)-methylpyrrolidine ring or (2S)-methylpyrrolidine ring.

12. The compound of claim 1, wherein the compound has the formula

13. The compound of claim 12, wherein R₁ is -L₂-R_6a-L₃-R_6b, wherein L₂ is a bond, R_6b is hydrogen, L₃ is a bond, R_6a is selected from a 5- or 6-membered heteroaryl ring, and R₄ and R₅ taken together with the nitrogen atom to which each is attached form a 4- to 8-membered non-aromatic ring represented by formula (a).

14. The compound of claim 1, wherein the compound has the formula

15. The compound of claim 14, wherein R₁ is -L₂-R_6a-L₃-R_6b, wherein L₂ is a bond, R_6b is hydrogen, L₃ is a bond, R_6a is selected from a 5- or 6-membered heteroaryl ring, and R₄ and R₅ taken together with the nitrogen atom to which each is attached form a 4- to 8-membered non-aromatic ring represented by formula (a).

16. The compound of claim 1, selected from the group consisting of

4′

-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-trans-cyclobutyl}-biphenyl-4-carbonitrile;

4′

-{3[(2R)-2-methyl-pyrrolidin-1-yl]-cis-cyclobutyl}-biphenyl-4-carbonitrile;

4′

-[3-(2-methyl-pyrrolidin-1-yl)-cis-cyclobutyl]-biphenyl-4-carbonitrile;

4′

-[3-(2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-biphenyl-4-carbonitrile;

5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-cis-cyclobutyl]-phenyl}-pyrimidine;

2,6-difluoro-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-cis-cyclobutyl]-phenyl}-pyridine;

2,6-difluoro-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyridine;

2,6-dimethyl-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyridine;

2,6-dichloro-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyridine;

4′

-{3-[(2S)-2-methyl-pyrrolidin-1-yl]-cis-cyclobutyl}-biphenyl-4-carbonitrile;

5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidine;

2-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-2H-pyridazin-3-one;

4′

-{3-[(2S)-2-methyl-pyrrolidin-1-yl]-trans-cyclobutyl}-biphenyl-4-carbonitrile;

5-{4-[3-({2S}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidine;

2,4-dimethoxy-5-{4-[3-({2S}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidine;

2-methoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidine;

2,4-dimethoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidine;

5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-nicotinonitrile;

2-methyl-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-benzothiazole;

2-methyl-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyridine;

1,3,5-trimethyl-4-{4-[3-(2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-1H-pyrazole;

5-{2-fluoro-4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidine;

4′

-{3-[(2R)-2-methyl-pyrrolidin-1-ylmethyl]-cis-cyclobutyl}-biphenyl-4-carbonitrile;

4′

-{3-[(2R)-2-methyl-pyrrolidin-1-ylmethyl]-trans-cyclobutyl}-biphenyl-4-carbonitrile;

4′

-{3-[(2S)-2-methyl-pyrrolidin-1-ylmethyl]-cis-cyclobutyl}-biphenyl-4-carbonitrile;

2,6-difluoro-3-{4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-pyridine;

5-{4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-pyrimidine;

4′

-[3-(2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-biphenyl-4-carbonitrile;

1,3,5-trimethyl-4-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-1H-pyrazole;

2-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-2H-pyridazin-3-one;

2-methoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-pyrimidine;

2,4-dimethoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-pyrimidine; and

4′

-{3-[(2R)-2-methyl-pyrrolidin-1-yl]-cis-cyclobutylmethyl}-biphenyl-4-carbonitrile.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.

18. A method of selectively modulating the effects of histamine-3 receptors in a mammal comprising administering an effective amount of a compound of claim 1.

19. A method of treating a condition or disorder modulated by the histamine-3 receptors in a mammal comprising administering an effective amount of a compound of claim 1.

20. The method according to claim 19, wherein the condition or disorder is selected from the group consisting of attention-deficit hyperactivity disorder (ADHD), deficits in attention, dementia, and diseases with deficits of memory, learning, schizophrenia, cognitive deficits of schizophrenia, cognitive deficits and dysfunction in psychiatric disorders, Alzheimer'"'"'s disease, mild cognitive impairment, epilepsy, seizures, allergic rhinitis, and asthma, motion sickness, dizziness, Meniere'"'"'s disease, vestibular disorders, vertigo, obesity, diabetes, type II diabetes, Syndrome X, insulin resistance syndrome, metabolic syndrome, pain, including neuropathic pain, neuropathy, sleep disorders, narcolepsy, pathological sleepiness, jet lag, drug abuse, mood alteration, bipolar disorder, depression, obsessive compulsive disorder, Tourette'"'"'s syndrome, Parkinson'"'"'s disease, and medullary thyroid carcinoma, melanoma, and polycystic ovary syndrome.