# US 11,306,069 B2 · Benzimidazole derivatives as dual histamine H1 and histamine H4 receptor ligands

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- Number: US 11,306,069 B2
- Document ID: US11306069B2
- Status: Granted
- Kind: B2
- Application number: 16/192,162
- Filed: 2018-11-15
- Published: 2019-05-16
- Granted: 2022-04-19
- Earliest claimed: 2017-11-15
- Assignees: Bioprojet
- Applicants: Bioprojet
- Inventors: Isabelle Berrebi-Bertrand; Xavier Billot; Thierry Calmels; Marc Capet; Stéphane Krief; Olivier Labeeuw; Jeanne-Marie Lecomte; Nicolas Levoin; Xavier Ligneau; Philippe Robert; Jean-Charles Schwartz
- Web page: https://patentgrep.com/patent/US11306069B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

Novel benzimidazole enantiomeric derivatives, their process of preparation and their therapeutical uses as dual H1 and H4 receptor ligands are disclosed.

## Claims

### Claim 1

A method of treating inflammation comprising administering to a patient in need thereof an (S)-enantiomer of formula (II):
wherein:
* denotes the asymmetric carbon exhibiting a defined (S)-enantiomer stereochemistry;
X represents H or F;
R1, R2, R3, and R4 are identical or different and independently represent H, halogen, alkyl or alkoxy; and
wherein one of X, R1, R2, R3, or R4 does not represent H;
or pharmaceutically acceptable salts, tautomers, hydrates, or solvates thereof;
wherein the (S)-enantiomer has H1 and H4 affinity.

### Claim 2 (depends on 1)

The method of claim 1 wherein the (S)-enantiomer is the anhydrous hydrochloride (form I) of (S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, and wherein the (S)-enantiomer has the following X-ray powder diffraction peaks: (characteristic peaks, 2θ in °): 8.6, 12.4, 13.1, 15.9, 16.8, 18.8, 19.9, 20.4, 21.3, 23.4, 25.0, 25.7, 26.3, 26.9, 28.4, and 30.1.

### Claim 3 (depends on 1)

The method of claim 1 wherein the (S)-enantiomer is the monohydrate hydrochloride (form II) of (S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, and wherein the (S)-enantiomer has the following X-ray powder diffraction peaks: (characteristic peaks, 2θ in °): 6.3, 13.7, 15.1, 15.7, 16.4, 20.3, 22.1, 24.4, and 29.1.

### Claim 4 (depends on 1)

The method according to claim 1 wherein at least X, R1, or R4 represents F.

### Claim 5 (depends on 1)

The method according to claim 1 wherein R1, R2, R3, or R4 independently represents alkyl or alkoxy.

### Claim 6 (depends on 1)

The method according to claim 1 wherein:
X═H or F;
R1═H; Me, F, Cl;
R2═H or C;
R3═H or F; and
R4═H.

### Claim 7 (depends on 1)

The method according to claim 1 wherein the (S)-enantiomer is selected from the group consisting of:
(S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol;
(S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, hydrochloride, monohydrate;
(S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, hydrochloride; and
(S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, (R)-para-methylmandelate.

### Claim 8

A method of treating inflammation comprising administering a pharmaceutical composition comprising the (S)-enantiomer of formula (II):
wherein:
* denotes the asymmetric carbon exhibiting a defined (S)-enantiomer stereochemistry;
X represents H or F;
R1, R2, R3, and R4 are identical or different and independently represent H, halogen, alkyl or alkoxy; and
wherein one of X, R1, R2, R3, or R4 does not represent H;
or pharmaceutically acceptable salts, tautomers, hydrates, or solvates thereof;
and a pharmaceutically acceptable excipient;
wherein the (S)-enantiomer has H1 and H4 affinity.

### Claim 9

A method of treating inflammation comprising administering to a patient in need thereof an (S)-enantiomer of formula (II):
wherein:
* denotes the asymmetric carbon exhibiting a defined (S)-enantiomer stereochemistry;
X represents H or F;
R1, R2, R3, and R4 are identical or different and independently represent H, halogen, alkyl or alkoxy; and
wherein one of X, R1, R2, R3, or R4 does not represent H;
or pharmaceutically acceptable salts, tautomers, hydrates, or solvates thereof;
wherein the (S)-enantiomer has H1 and H4 affinity.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the (S)-enantiomer of formula (II) is administered in the form of a pharmaceutical composition comprising the (S)-enantiomer of formula (II) and a pharmaceutically acceptable excipient.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the inflammation occurs in a disorder selected from the group consisting of anaphylactic shock, respiratory inflammatory and allergic diseases, adult respiratory distress syndrome, acute respiratory distress syndrome, respiratory infections, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, rhinorrhea, chronic sinusitis, allergy, allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, conjunctivitis, allergic conjunctivitis, otitis, nasal polyps, vaugh, ocular itching, chronic urticaria, eczema, prurigo, pruritus cutaneous, erythema exsudativum, nasal congestion, allergic congestion; dermatological diseases, dermatitis, atopic dermatitis, psoriasis and itchy skin; pruritus, skin incision model of postoperative pain, allergic skin disease/itching and inflammation, allergic contact dermatitis, itching associated with hepatic or kidney insufficiency; pain, neuropathic pain, chronic hyper-eosinophilias, chronic diseases associated with mast cell multiplication; and lymphatic diseases.

### Claim 12 (depends on 8)

The method according to claim 8, wherein the inflammation occurs in a disorder selected from the group consisting of anaphylactic shock, respiratory inflammatory and allergic diseases, adult respiratory distress syndrome, acute respiratory distress syndrome, respiratory infections, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, rhinorrhea, chronic sinusitis, allergy, allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, conjunctivitis, allergic conjunctivitis, otitis, nasal polyps, vaugh, ocular itching, chronic urticaria, eczema, prurigo, pruritus cutaneous, erythema exsudativum, nasal congestion, allergic congestion; dermatological diseases, dermatitis, atopic dermatitis, psoriasis and itchy skin; pruritus, skin incision model of postoperative pain, allergic skin disease/itching and inflammation, allergic contact dermatitis, itching associated with hepatic or kidney insufficiency; pain, neuropathic pain, chronic hyper-eosinophilias, chronic diseases associated with mast cell multiplication; and lymphatic diseases.

### Claim 13 (depends on 9)

The method according to claim 9, wherein the inflammation occurs in a disorder selected from the group consisting of anaphylactic shock, respiratory inflammatory and allergic diseases, adult respiratory distress syndrome, acute respiratory distress syndrome, respiratory infections, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, rhinorrhea, chronic sinusitis, allergy, allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, conjunctivitis, allergic conjunctivitis, otitis, nasal polyps, vaugh, ocular itching, chronic urticaria, eczema, prurigo, pruritus cutaneous, erythema exsudativum, nasal congestion, allergic congestion; dermatological diseases, dermatitis, atopic dermatitis, psoriasis and itchy skin; pruritus, skin incision model of postoperative pain, allergic skin disease/itching and inflammation, allergic contact dermatitis, itching associated with hepatic or kidney insufficiency; pain, neuropathic pain, chronic hyper-eosinophilias, chronic diseases associated with mast cell multiplication; and lymphatic diseases.