# US 12,600,715 B2 · Soluble guanylate cyclate activators for treating systemic sclerosis

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- Number: US 12,600,715 B2
- Document ID: US12600715B2
- Status: Granted
- Kind: B2
- Application number: 18/386,267
- Filed: 2023-11-02
- Published: 2024-05-30
- Granted: 2026-04-14
- Earliest claimed: 2022-11-04
- Assignees: Boehringer Ingelheim International GmbH
- Applicants: Boehringer Ingelheim International GmbH
- Inventors: Mary Ruth Flack; Julia Kaufman; Indra Sethy-Coraci
- Web page: https://patentgrep.com/patent/US12600715B2

## CPC

- A61K 31/553: having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
- C07D 405/14: containing three or more hetero rings
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to methods for treating patients with systemic sclerosis, comprising administering to a patient in need thereof a therapeutically effective amount of a soluble guanylate cyclase (sGC) activator of formula (I), or a pharmaceutically acceptable salt thereof, where R1-R7 and A are as defined herein.

## Claims

### Claim 1

A method for treating a patient with systemic sclerosis, comprising administering to the patient a therapeutically effective amount of a compound of formula (I),
wherein:
A is a 5-7 membered saturated heterocyclyl group containing one nitrogen and optionally one oxygen, wherein one carbon of said heterocyclyl group is optionally substituted with one or two groups selected from C1-3alkyl and oxo;
R1 is C1-4 alkyl optionally substituted with a methoxy group;
R2 is selected from H, F, Cl, C1-3alkyl, —CN, —OMe and —CF3;
R3 is selected from H and —CH3;
R4 is selected from H, F, —CH3 and —OMe;
R5 is selected from H, Cl, —CH3, —CH2CH3, —CF3, F, and —OMe;
R6 is bonded to the nitrogen on A and is selected from H, C1-6alkyl, —(CH2)nC3-6cycloalkyl, —C(O)C1-6alkyl, —(CH2)n heterocyclyl, —(CH2)n aryl —(CH2)n heteroaryl, —SO2aryl, SO2C1-6alkyl wherein said C1-6alkyl, —(CH2)n heterocyclyl, —(CH2)n C3-6cycloalkyl, —(CH2)n aryl and —(CH2)n heteroaryl are optionally substituted with one to four groups independently selected from C1-3alkyl, halogen, C1-3alkoxy, —CF3, —OH, oxo, —(CH2)1-3OH(CH2)2-3OH, and —SO2CH3;
R7 is selected from H, —CH3, —CH2CH3, —CF3, F, and —CN;
n is 0, 1 or 2
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the patient has early diffuse cutaneous systemic sclerosis (dcSSc) and/or vasculopathy.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the compound of formula (I) is administered to the patient in an amount selected from the group consisting of 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4, mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, and 10 mg.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the compound of formula (I) is administered to the patient two times a day (BID) or three times a day (TID).

### Claim 5 (depends on 1)

The method according to claim 1, wherein the compound of formula (I) is orally administered to the patient in amount selected from the group consisting of 1 mg, 2 mg, 3 mg, and 4 mg.

### Claim 6 (depends on 5)

The method according to claim 5, where the compound of formula (I) is administered to the patient in an amount of 1 mg three times a day (TID), or in an amount of 2 mg TID, or an amount of 3 mg TID, or an amount of 4 mg TID.

### Claim 7 (depends on 1)

The method of claim 1, wherein the treatment comprises an initiation treatment comprising administering the compound of formula (I) in an amount of 1 mg three times a day (TID) for weeks one and two; followed by 2 mg TID for weeks 3 and 4 weeks, followed by 3 mg for week 5 until the end of treatment.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the amount of the compound of formula (I) is decreased if the patient develops symptomatic orthostatic hypotension.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the treatment produces an improvement in:
rate of decline in FVC (mL) over 48 weeks over placebo,
change from baseline in mRSS at Week 48,
revised CRISS score at Week 48,
change from baseline in HAQ-DI score at Week 48,
change from baseline in the PGA VAS score at Week 48,
change from baseline in the CGA VAS score at Week 48,
composite measure of RP activity at Week 48,
change from baseline in DU net burden at Week 48, and/or
time to treatment failure, defined as the time to one of the following events occurring over the 48-week and extended treatment period selected from the group consisting of:
death,
absolute decline in percent-predicted FVC≥10% relative to baseline,
≥25% increase in mRSS and an increase in mRSS of >5 points, and
initiation or dose change of immunomodulating/immunosuppressive therapy for clinically significant deterioration of dcSSc.

### Claim 10 (depends on 1)

The method according to claim 1, wherein the treatment produces an improvement in:
absolute change from baseline in the FACIT—Fatigue Scale score at Week 48,
absolute change from baseline in SSPRO score at Week 48,
absolute change from baseline in EQ-5D-5L score at Week 48,
absolute change from baseline in Worst Pain NRS at Week 48,
absolute change from baseline in the six individual SHAQ domain scores (pain, intestinal problems, respiratory problems, RP, finger ulcers, disease severity) at Week 48,
PGIC score at Week 48,
change from baseline in DLCO in percent predicted at Week 48,
Global Rank Composite Score (GRCS) at the end of the extended treatment period or at the end of the 48-week primary assessment treatment period versus patients who do not participate in the extended treatment period,
annual rate of decline in FVC (mL) over the Primary Assessment Treatment Period and extended treatment period
change from baseline in presence or absence tendon friction rubs at Week 48,
change from baseline in joint involvement at Week 48, and/or
absolute change from baseline in RCS at Week 48.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the compound of formula (I) has the structure:

### Claim 12

A method for treating a patient with systemic sclerosis, comprising administering to the patient a therapeutically effective amount of a compound having the
wherein the compound is orally administered to the patient in amount of amount 1 mg, 2 mg, 3 mg, or 4 mg.

### Claim 13 (depends on 12)

The method according to claim 12, wherein the compound is administered to the patient two times a day (BID) or three times a day (TID).

### Claim 14 (depends on 12)

The method according to claim 12, where the compound is administered to the patient in an amount of 1 mg three times a day (TID), or in an amount of 2 mg TID, or an amount of 3 mg TID, or an amount of 4 mg TID.

### Claim 15 (depends on 12)

The method of claim 12, wherein the treatment comprises an initiation treatment comprising administering the compound in an amount of 1 mg three times a day (TID) for weeks one and two; followed by 2 mg TID for weeks 3 and 4 weeks, followed by 3 mg (TID) for week 5 until the end of treatment.

### Claim 16 (depends on 12)

The method according to claim 12, wherein the amount of the compound is decreased if the patient develops symptomatic orthostatic hypotension.

### Claim 17 (depends on 12)

The method according to claim 12, wherein the treatment produces an improvement in:
rate of decline in FVC (mL) over 48 weeks over placebo,
change from baseline in mRSS at Week 48,
revised CRISS score at Week 48,
change from baseline in HAQ-DI score at Week 48,
change from baseline in the PGA VAS score at Week 48,
change from baseline in the CGA VAS score at Week 48,
composite measure of RP activity at Week 48,
change from baseline in DU net burden at Week 48, and/or
time to treatment failure, defined as the time to one of the following events
occurring over the 48-week and extended treatment period selected from the group consisting of:
death,
absolute decline in percent-predicted FVC ≥10% relative to baseline,
≥25% increase in mRSS and an increase in mRSS of >5 points, and
initiation or dose change of immunomodulating/immunosuppressive
therapy for clinically significant deterioration of dcSSc.

### Claim 18 (depends on 12)

The method according to claim 12, wherein the treatment produces an improvement in:
absolute change from baseline in the FACIT-Fatigue Scale score at Week 48,
absolute change from baseline in SSPRO score at Week 48,
absolute change from baseline in EQ-5D-5L score at Week 48,
absolute change from baseline in Worst Pain NRS at Week 48,
absolute change from baseline in the six individual SHAQ domain scores (pain, intestinal problems, respiratory problems, RP, finger ulcers, disease severity) at Week 48,
PGIC score at Week 48,
change from baseline in DLCO in percent predicted at Week 48,
Global Rank Composite Score (GRCS) at the end of the extended treatment period or at the end of the 48-week primary assessment treatment period versus patients who do not participate in the extended treatment period,
annual rate of decline in FVC (mL) over the Primary Assessment Treatment Period and extended treatment period
change from baseline in presence or absence tendon friction rubs at Week 48,
change from baseline in joint involvement at Week 48, and/or absolute change from baseline in RCS at Week 48.

### Claim 19 (depends on 12)

The method of claim 12, wherein the patient has early diffuse cutaneous systemic sclerosis (dcSSc) and/or vasculopathy.

### Claim 20

A method for treating a patient with systemic sclerosis, comprising administering to the patient a compound having the formula:
wherein the compound is administered orally as a pharmaceutical composition comprising 1 mg, 2 mg, 3 mg or 4 mg of the compound.