4-Aryliquinazolines and the use thereof as nhe-3 inhibitors

• US 20050020612A1
• Filed: 11/29/2002
• Published: 01/27/2005
• Est. Priority Date: 12/24/2001
• Status: Abandoned Application

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Gericke, Rolf
• Application Number:
  US10/499,972
• Publication Number:
  US 20050020612A1
• Time in Patent Office: Days
• US Class Current: 514/266.400
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/12 of the kidneys
• 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 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• 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 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: C07D 239/84 Nitrogen atoms

Abstract

The invention relates to compounds of the formula (I) in which Ar is X-substituted phenyl or naphthyl, which is additionally substituted by R³ and R⁴, Y or X is H, NR⁶R⁷ or a saturated 5-7-membered ring having two N atoms, R¹, R², R³ and R⁴ are each, independently of one another, H, A, OA, Hal, CF₃, OH, NO₂, NH₂, NHA, NA₂, NH—CO-A, NH—CO-Ph, SA, SO-A, SO₂-A, SO₂-Ph, CN, OCF₃, CO-A, CO₂H, CO₂A, CO—NH₂, CO—NHA, CO—NA₂, SO₂NH₂, SO₂NHA, SO₂NA₂, or phenyl which is unsubstituted or monosubstituted or polysubstituted by A, OA, Hal or CF3, and salts and solvates thereof, and to the use thereof as NHE-3 inhibitors.

Claims

1. Compounds of the formula I

2. Compounds of the formula I according to claim 1, characterised in that Ar has one of the following meanings:

3. Compounds of the formula I according to claim 1, characterised in that at least one of the radicals R¹, R², R³ and R⁴ has one of the following meanings:

Hal, A, OH, NO₂, NH₂, NHA, NA₂, NH—

CO-A, NH—

CO-Ph, SA, SO-A, SO₂-A, SO₂-Ph, CN, OCF₃, CO-A, CO₂H, CO₂A, CO—

NH₂, CO—

NHA, CO—

NA₂, SO₂NH₂, SO₂NHA, SO₂NA₂, or phenyl which is unsubstituted or monosubstituted or polysubstituted by A, OA, Hal or CF₃.

4. Compounds of the formula I according to claim 1, characterised in that R⁵ is H, A, OH, NO₂ or an amino-protecting group.

5. Compounds of the formula I according to claim 1, characterised in that R⁶ and R⁷ are simultaneously H, independently of one another H, A, benzyl or —

(CH₂)_nNA₂.

6. Compounds of the formula I according to claim 1, characterised in that R⁸ and R⁹ are H or methyl.

7. Compounds of the formula I according to claim 1, characterised in that R¹⁰ and R¹¹ are H, A, benzyl or phenyl.

8. Compounds of the formula I according to claim 1, characterised in that X is NR⁶R⁷, a 5- to 7-membered ring having 2 N atoms or the following radical:

9. Compounds of the formulae IA, IB and IC:

10. Compounds of the formulae IA, IB and IC according to claim 9, in which R² is Cl.

12. Compounds of the formula I according to one or more of the preceding claims and their salts and/or solvates as NHE-3 inhibitors.

13. Compounds of the formula I according to claim 1 and their physiologically acceptable salts and/or solvates for use in combating illnesses.

14. Use of compounds of the formula I according to claim 1 and/or their physiologically acceptable salts or solvates for the preparation of a medicament.

15. Use of compounds of the formula I according to claim 1 and/or their physiologically acceptable salts and/or solvates for the preparation of a medicament for the treatment and prophylaxis of hypertonia, thrombosis, ischaemic states of the heart, of the peripheral and central nervous system and of strokes, ischaemic states of peripheral organs and limbs, and for the treatment of shock states.

16. Use of compounds of the formula I according to claim 1 and/or their physiologically acceptable salts and/or solvates for the preparation of a medicament for use in surgical operations and organ transplants and for the preservation and storage of transplants for surgical measures.

17. Use of compounds of the formula I according to claim 1 and/or their physiologically acceptable salts and/or solvates for the preparation of a medicament for the treatment and prophylaxis of illnesses in which cell proliferation represents a primary or secondary cause, for the treatment or prophylaxis of disorders of fat metabolism or disturbed breathing drive.

18. Use of compounds of the formula I according to claim 1 and/or and their physiologically acceptable salts and/or solvates for the preparation of a medicament for the treatment and prophylaxis of renal ischaemia, ischaemic intestinal illnesses or for the prophylaxis of acute or chronic renal illnesses.

19. Use of compounds of the formula I according to claim 1 and/or their physiologically acceptable salts and/or solvates for the preparation of a medicament for the treatment and prophylaxis of bacterial and parasitic illnesses.

20. Pharmaceutical preparation, characterised by a content of at least one NHE-3 inhibitor according to claim 1 and/or one of its physiologically acceptable salts and/or solvates.

21. Process for the preparation of pharmaceutical preparations, characterised in that at least one compound of the formula I according to claim 1 and/or one of its physiologically acceptable salts and solvates is converted into a suitable dosage form together with at least one solid, liquid or semi-liquid excipient or adjuvant.

22. Use of compounds of the formula I according to claim 1 and/or physiologically acceptable salts and/or solvates thereof for the preparation of a medicament for the treatment and prophylaxis of diseases which are caused by increased NHE activity and/or can be influenced by a reduction in NHE activity.

23. Use of compounds of the formula I according to claim 1 and/or physiologically acceptable salts and/or solvates thereof for the preparation of a medicament for the treatment and prophylaxis of diseases or states which are caused by increased uptake of sodium ions and water in cells by organs which are undersupplied with oxygen.

24. Medicament comprising at least one compound of the formula I according to claim 1 and/or physiologically acceptable salts and solvates thereof and at least one further medicament active ingredient.

25. Set (kit) consisting of separate packs of

(a) an effective amount of a compound of the formula I according to claim 1 and/or physiologically acceptable salts and solvates thereof and

(b) an effective amount of a further medicament active ingredient.

26. Compounds according to claim 1 as medicament active ingredients.

27. Process for the preparation of the compounds of the formula I and salts and solvates thereof, characterised in that either

(a)

compounds of the formula II

 

in which R¹, R² and Ar are as defined in claim 1,

are reacted with 1-cyanoguanidine or a correspondingly N-alkylated or N-arylated 1-cyanoguanidine of the formula NC—

Y, in which Y is as defined in claim 1 and z is 0, or

(b)

instead of a compound of the formula NC—

Y, a compound of the formula III

HN═

CX—

Y 

 

III

 

in which X is —

S-alkyl, —

S-aryl, —

O-alkyl or —

O-aryl, and Y is as defined in claim 1, where z is 0, is reacted with a compound of the formula II, or

(c)

compounds of the formula IV

 

in which Ar, Hal, R¹ and R² are as defined above,

are reacted with a compound of the formula HY, in which Y is as defined in claim 1, or

(d)

compounds of the formula VI

 

are amidated using the corresponding nitrogen bases with palladium catalysis,

and if desired, after steps (a), (b), (c) or (d), a basic or acidic compound of the formula I is converted into one of its salts or solvates by treatment with an acid or base.

11. Compounds of the formulae I1 to I10 and salts and solvates thereof: