Compounds containing S-N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and cations

• US 8,877,938 B2
• Filed: 11/08/2006
• Issued: 11/04/2014
• Est. Priority Date: 11/09/2005
• Status: Active Grant

• Current Assignee: Novartis Pharmaceuticals Corporation (Novartis Ag)
• Original Assignee: Novartis Pharmaceuticals Corporation (Novartis Ag)
• Inventors: Feng, Lili, Godtfredsen, Sven Erik, Hu, Bin, Liu, Yugang, Karpinski, Piotr, Sutton, Paul Allen, Prashad, Mahavir, Girgis, Michael J., Blacklock, Thomas J.
• Primary Examiner(s): THOMAS, TIMOTHY P
• Application Number:
  US11/722,360
• Publication Number:
  US 20090156585A1
• Time in Patent Office: 2,918 Days
• Field of Search: 548/253, 514/381
• US Class Current: 548/253
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/4422 1,4-Dihydropyridines, e.g. nifedipine, nicardipine
• CPC Class Codes: A61K 31/5415 ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• 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 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/24 : of the sex hormones
• CPC Class Codes: A61P 5/42 : for decreasing, blocking or antagonising the activity of mineralocorticosteroids
• 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 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• 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: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07C 233/47 : having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07D 207/50 : Nitrogen atoms
• CPC Class Codes: C07D 257/04 : Five-membered rings

Abstract

A compound of an angiotensin receptor antagonist (ARB), a neutral endopeptidase inhibitor (NEPi) and one or more monovalent cations are useful for the treatment of hypertension and/or heart failure. ARB includes S—N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine in the anion form, NEPi includes (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester in the anion form and cation includes monovalent cations such as Na⁺. The compound includes trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate] hemipentahydrate.

Claims

1. Trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′

-methyl-2′

-(pentanoyl{2″

-(tetrazol-5-ylate)biphenyl-4′

-ylmethyl}amino)butyrate] hemipentahydrate in crystalline form.

2. The compound of claim 1 having the sum formula C₄₈H₅₅N₆O₈Na₃ ●

2.5 H₂O and being in the form of an asymmetric unit comprising six C₄₈H₅₅N₆O₈Na₃ ●

2.5 H₂O formula units.

3. The compound of claim 1 characterized by an Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) spectrum having the following absorption bands expressed in reciprocal wave numbers (cm⁻

1)(±

2 cm<sup>−

1</sup>);

1711 (st), 1637 (st), 1597 (st) and 1401 (st).

4. The compound of claim 3 characterized by an Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) spectrum having the following absorption bands expressed in reciprocal wave numbers (cm⁻

1)(±

2 cm<sup>−

1</sup>);

2956 (w), 1711 (st), 1637 (st), 1597 (st), 1488 (w), 1459 (m), 1401 (st), 1357 (w), 1295 (m), 1266 (m), 1176 (w), 1085 (m), 1010 (w), 942 (w), 907 (w), 862 (w), 763 (st), 742 (m), 698 (m), 533 (st).

5. The compound of claim 1 characterized by an X-ray powder diffraction pattern taken with a Scintag XDS2000 powder diffractometer comprising the following interlattice plane intervals:

d in [Å

] (±

0.1 Å

);

21.2(s), 17.0(w), 7.1(s), 5.2(w), 4.7(w), 4.6(w), 4.2(w), 3.5(w), 3.3(w).

6. The compound of claim 1 characterized by an X-ray powder diffraction pattern taken with a Scintag XDS2000 powder diffractometer comprising the following interlattice plane intervals:

2θ

in [°

] 4.5, 5.5, 5.6, 9.9, 12.8, 15.7, 17.0, 17.1, 17.2, 18.3, 18.5, 19.8, 21.5, 21.7, 23.2, 23.3, 24.9, 25.3, 27.4, 27.9, 28.0, 30.2.

7. The compound of claim 1 in the form of a monoclinic unit cell, wherein its cell content comprises twelve formula units of C₄₈H₅₅N₆O₈Na₃ ●

2.5 H₂O.

8. The compound of claim 7 in the form of a monoclinic unit cell, wherein the cell content of the monoclinic unit cell comprises two asymmetric units on two-fold positions.

9. The compound of claim 7 wherein the monoclinic unit cell has a P2i space group.

10. The compound of claim 1 characterized by

11. A pharmaceutical composition comprising an effective amount of the compound of claim 1 and at least one pharmaceutically acceptable additive.

12. The pharmaceutical composition of claim 10 further comprising a therapeutic agent selected from an anti-diabetic, a hypolipidemic agent, an anti-obesity agent and an anti-hypertensive agent.

13. The pharmaceutical composition of claim 11 wherein the therapeutic agent is amlodipine besylate.

14. The pharmaceutical composition of claim 11, wherein the therapeutic agent is hydrochlorothiazide.