Benzoimidazol-2-yl pyrimidine modulators of the histamine H4 receptor

• US 9,663,497 B2
• Filed: 08/03/2016
• Issued: 05/30/2017
• Est. Priority Date: 03/06/2013
• Status: Active Grant

• Current Assignee: Novassay S.A.
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Hickey, Magali B., Conza, Matteo, Horns, Stefan, Lochner, Susanne
• Primary Examiner(s): VAJDA, KRISTIN ANN
• Application Number:
  US15/227,878
• Publication Number:
  US 20160340337A1
• Time in Patent Office: 300 Days
• Field of Search: 544331, 514275
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• 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 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/22 : for herpes viruses
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 33/14 : Ectoparasiticides, e.g. scabicides
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• 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: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/16 : for decreasing, blocking or antagonising the activity of the thyroid hormones
• CPC Class Codes: A61P 5/38 : of the suprarenal hormones
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/12 : Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• 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: C07B 2200/13 : Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07C 51/43 : by change of the physical state, e.g. crystallisation
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C30B 29/54 : Organic compounds
• CPC Class Codes: C30B 7/08 : by cooling of the solution

Abstract

Benzoimidazol-2-yl pyrimidines, purification methods for the same, and pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by H₄ receptor activity, including allergy, asthma, autoimmune diseases, and pruritus.

Claims

1. A method of obtaining a purified pharmaceutically acceptable salt of a [5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine, comprising:

forming a hemitartrate salt of the compound of formula (2);

2. A method as in claim 1, wherein said third crystallizing is performed once, and said tetrahydrate hemitartrate of formula (3) has a purity of at least about 99%.

3. A method as in claim 1, wherein said third crystallizing is performed once, and said tetrahydrate hemitartrate of formula (3) has a purity of at least about 99.5%.

4. A method as in claim 1, wherein third crystallizing is performed once, and said tetrahydrate hemitartrate of formula (3) has a purity of at least about 99.8%.

5. A method as in claim 1, further comprising:

dissolving said tetrahydrate hemitartrate of formula (3) in water to form an aqueous tetrahydrate hemitartrate product solution;

seeding said aqueous tetrahydrate hemitartrate product solution with crystal seeds of the tetrahydrate of said hemitartrate; and

a fourth crystallizing said aqueous tetrahydrate hemitartrate product solution to yield a re-crystallized tetrahydrate hemitartrate of formula (3).

6. A method as in claim 5, wherein said fourth crystallizing is performed once, and said re-crystallized tetrahydrate hemitartrate of formula (3) has a purity of at least about 99.9%.

7. A method as in claim 2, further comprising:

dissolving said hemitartrate in water to yield an aqueous hemitartrate solution;

seeding said aqueous solution with crystal seeds of the tetrahydrate of said hemitartrate; and

a second crystallizing said aqueous hemitartrate solution to form the solid tetrahydrate hemitartrate of formula (3);

8. A method as in claim 7, wherein said third crystallizing is performed once, and said tetrahydrate hemitartrate of formula (3) has a purity of at least about 99%.

9. A method as in claim 7, further comprising:

dissolving said tetrahydrate hemitartrate of formula (3) in water to form an aqueous tetrahydrate hemitartrate product solution;

seeding said aqueous tetrahydrate hemitartrate product solution with crystal seeds of the tetrahydrate of said hemitartrate; and

a third crystallizing said aqueous tetrahydrate hemitartrate product solution to yield a re-crystallized tetrahydrate hemitartrate of formula (3).

10. A method as in claim 7, wherein said third crystallizing is performed once, and said re-crystallized tetrahydrate hemitartrate of formula (3) has a purity of at least about 99.5%.

11. A method as in claim 1, wherein said third crystallizing comprises performing the following operations with said aqueous hemitartrate solution:

Stirring at about 35-40°

C. for about four hours, and cooling to about 5°

C.

12. A method as in claim 5, wherein said fourth crystallizing comprises performing the following operations with said product solution:

Keeping it at about 40°

C. for about one hour, and subsequently cooling to about 5°

C.

13. A method as in claim 7, wherein said second crystallizing comprises performing the following operations with said aqueous hemitartrate solution:

Stirring at about 35-40°

C. for about one hour, and subsequently cooling to about 5°

C.

14. A method as in claim 9, wherein said third crystallizing comprises performing the following operations with said aqueous hemitartrate solution:

Keeping it at about 40°

C. for about one hour, and subsequently cooling to about 5°

C.