# US 11,026,925 B2 · Angiotensin II receptor antagonist metabolite and NEP inhibitor composite and preparation method thereof

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- Number: US 11,026,925 B2
- Document ID: US11026925B2
- Status: Granted
- Kind: B2
- Application number: 16/071,377
- Filed: 2017-01-19
- Published: 2020-02-27
- Granted: 2021-06-08
- Earliest claimed: 2016-01-20
- Assignees: Shenzhen Salubris Pharmaceuticals Co., Ltd.
- Applicants: Shenzhen Salubris Pharmaceuticals Co. Ltd
- Inventors: Jie Yan; Wenjie Xu; Jianqiong Zhi; Song Li; Yang Wang; Yanxin Zheng
- Web page: https://patentgrep.com/patent/US11026925B2

## CPC

- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61K 31/197: the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid (carnitine A61K31/205)
- A61K 31/216: of acids having aromatic rings, e.g. benactizyne, clofibrate
- A61K 31/41: having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K 47/55: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- C07C 231/12: by reactions not involving the formation of carboxamide groups
- 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
- C07D 403/10: linked by a carbon chain containing aromatic rings
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Provided are a supramolecular composite comprising an angiotensin II receptor (AT1) blocking compound, a neutral endopeptidase inhibitor (NEPi), and a pharmaceutically acceptable cation. The invention further provides a method for preparing the composite and an application of the composite for preparing a pharmaceutical product for treating heart failure.

## Claims

### Claim 1

A supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor, wherein the formula unit of the supramolecular complex is:
(aEXP3174.bAHU377).xCa.nA,
wherein the molar ratio of a to b is from 1:0.25 to 1:4, x is from 0.5 to 3, A is water, methanol, ethanol, 2-propyl alcohol, acetone, ethyl acetate, methyl-tert-butyl ether, acetonitrile, methylbenzene or dichloromethane, and n is from 0 to 3.

### Claim 2 (depends on 1)

The supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor according to claim 1, wherein the formula unit of the supramolecular complex is:
(EXP3174.AHU377).xCa.nH2O,
wherein x is from 0.5 to 2, and n is from 0 to 3.

### Claim 3 (depends on 2)

The supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor according to claim 2, wherein x is from 1.5 to 2 and n is from 1 to 3.

### Claim 4 (depends on 2)

The supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor according to claim 2, wherein n is from 2 to 3.

### Claim 5 (depends on 1)

The supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor according to claim 1, wherein the formula unit of the supramolecular complex is:
(EXP3174.AHU377).1.5Ca.nH2O,
wherein n is from 1 to 3.

### Claim 6 (depends on 5)

The supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor according to claim 5, wherein n is from 2 to 3.

### Claim 7 (depends on 1)

The supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor according to claim 1, wherein the formula unit of the supramolecular complex is:
(EXP3174.AHU377).2Ca.nH2O,
wherein n is from 1 to 3.

### Claim 8 (depends on 7)

The supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor according to claim 7, wherein n is from 2 to 3.

### Claim 9 (depends on 1)

The supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor according to claim 1, wherein the formula unit of the supramolecular complex is any one of:
(EXP3174.AHU377).1.5Ca.1H2O
(EXP3174.AHU377).1.5Ca.1.5H2O
(EXP3174.AHU377).1.5Ca.2H2O
(EXP3174.AHU377).1.5Ca.2.5H2O
(EXP3174.AHU377).1.5Ca.3H2O
(EXP3174.AHU377).2Ca.1H2O
(EXP3174.AHU377).2Ca.1.5H2O
(EXP3174.AHU377).2Ca.2H2O
(EXP3174.AHU377).2Ca.2.5H2O, and
(EXP3174.AHU377).2Ca.3H2O.

### Claim 10 (depends on 1)

The supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor according to claim 1, wherein an XRD spectrum of the supramolecular complex shows diffraction peaks at 4.35°, 5.15°, 5.90°, 12.80° and 15.85° with an acceptable error range of ±0.2°, or wherein an XRD spectrum of the supramolecular complex shows diffraction peaks at 4.40°, 5.19° and 5.96° with an acceptable error range of ±0.2°.

### Claim 11 (depends on 10)

The supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor according to claim 10, wherein the XRD spectrum of the supramolecular complex that shows diffraction peaks at 4.35°, 5.15°, 5.90°, 12.80° and 15.85° with an acceptable error range of ±0.2° also shows diffraction peaks at 9.00°, 10.15° and 15.02° with an acceptable error range of ±0.2°, or wherein the XRD spectrum of the supramolecular complex that shows diffraction peaks at 4.40°, 5.19° and 5.96° with an acceptable error range of ±0.2° also shows diffraction peaks at 15.82° and 26.34° with an acceptable error range of ±0.2°.

### Claim 12 (depends on 10)

The supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor according to claim 10, wherein the XRD spectrum of the supramolecular complex shows diffraction peaks of:
Number
2θ (°, ±0.2)
Relative intensity (%)
1
4.35
70.97
2
5.15
100.00
3
5.90
32.67
4
9.00
2.80
5
10.15
3.40
6
12.80
5.21
7
15.02
5.59
8
15.85
8.27
9
16.81
2.57
10
20.27
2.39
11
22.09
2.48
12
23.79
1.34
13
26.22
1.87
or wherein the XRD spectrum of the supramolecular complex shows diffraction peaks of:
Number
2θ (°, ±0.2)
Relative intensity (%)
1
4.40
77.30
2
5.19
100.00
3
5.96
19.78
4
15.82
5.11
5
26.34
3.44

### Claim 13 (depends on 10)

The supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor according to claim 10, wherein the XRD spectrum of the supramolecular complex is as shown in FIG. 1 or FIG. 5.

### Claim 14 (depends on 1)

The supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor according to claim 1, wherein a DSC spectrum of the supramolecular complex shows two dehydration endothermic peaks at 94.4±10° C. and 164.1±10° C., and an endothermic peak in the spectrum at 244.6±5° C.; or wherein a DSC spectrum of the supramolecular complex shows two dehydration endothermic peaks at 95.4±10° C. and 166.4±10° C., and an endothermic peak in the spectrum at 242.4±5° C.

### Claim 15 (depends on 14)

The supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor according to claim 14, wherein the DSC spectrum of the supramolecular complex is as shown in FIG. 2 or FIG. 6.

### Claim 16 (depends on 1)

A composition comprising a supramolecular complex of an angiotensin II receptor metabolite and a NEP inhibitor according to claim 1 and a pharmaceutically acceptable carrier.

### Claim 17 (depends on 1)

A method of treating heart failure or hypertension in a patient comprising administering to said patient a drug preparation comprising the supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor according to claim 1 and a carrier.

### Claim 18 (depends on 17)

The method according to claim 17, wherein the mass percentage of the supramolecular complex in the drug is 0.1-99.9%.

### Claim 19 (depends on 1)

A method of preparing a supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor according to claim 1, comprising:
1) freeing a salt of AHU377 to provide AHU377;
2) dissolving the AHU377 1) and EXP3174 in a first solvent;
3) dissolving or suspending a pharmaceutically acceptable calcium ionic salt in a second solvent;
4) adding the solution or suspension of 3) to the solution of 2) and, optionally, adding a calcium ionic salt in a solid form to the mixture;
5) stirring the mixture, filtering the mixture to obtain a solid, and drying the solid to provide a supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor according to claim 1,
wherein
the salt of AHU377 is selected from a calcium salt, a magnesium salt, a zinc salt, a ferric salt, a sodium salt, an ammonium salt, a diethylammonium salt, or a triethylammonium salt,
the first solvent is isopropyl acetate,
the molar ratio of EXP3174 to AHU377 in 2) is 0.7-1.2:1,
the molar ratio of quantity of calcium ion in calcium ionic salt to AHU377 is 1.3-2.1:1,
the second solvent comprises acetone and/or isopropanol and a suitable quantity of water, wherein a weight/volume ratio of AHU377 to water is 1-8:1 g/ml,
the formula unit of the supramolecular complex obtained from the reaction is (EXP3174.AHU377).1.5Ca.2.5H2O, and
the reaction temperature in step 4) is between room temperature and 45° C.

### Claim 20 (depends on 19)

The method according to claim 19, wherein the weight/volume ratio of AHU377 to water is 2.36:1 g/ml.

### Claim 21 (depends on 1)

A method of preparing a supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor according to claim 1, comprising:
1) freeing a salt of AHU377 to provide AHU377;
2) dissolving the AHU377 of 1) and EXP3174 in a solvent;
3) adding a calcium ionic salt in a solid form in a solid form to the solution of 2);
4) stirring the mixture, filtering the mixture to obtain a solid, and drying the solid to provide a supramolecular complex of angiotensin II receptor metabolite and NEP inhibitor according to claim 1,
wherein
the salt of AHU377 is selected from a calcium salt, a magnesium salt, a zinc salt, a ferric salt, a sodium salt, an ammonium salt, a diethylammonium salt, or a triethylammonium salt,
the solvent comprises isopropyl acetate and sufficient water, wherein a weight/volume ratio of AHU377 to water is 1-8:1 g/ml,
the molar ratio of EXP3174 to AHU377 is 0.7-1.2:1;
the molar ratio of quantity of calcium ion in calcium ionic salt to AHU377 is 1.3-2.1:1,
the formula unit of the supramolecular complex obtained from the reaction is (EXP3174.AHU377).1.5Ca.2H2O, and
the reaction temperature in 3) is between room temperature and 45° C.

### Claim 22 (depends on 21)

The method according to claim 21, wherein the weight/volume ratio of AHU377 to water is 3.93:1 g/ml.