# US 2021/0275502 A1 · Process for preparing a potent thiazole compound, pharmaceutical formulation and uses thereof

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- Number: US 2021/0275502 A1
- Document ID: US20210275502A1
- Status: Published application
- Kind: A1
- Application number: 17/050,431
- Filed: 2019-04-26
- Published: 2021-09-09
- Earliest claimed: 2018-04-27
- Assignees: Ahammune Biosciences Private Limited
- Applicants: Ahammune Biosciences Private Limited
- Inventors: Parul GANJU; Sudhanand PRASAD; Mahesh Kumar VERMA; Kashinath KOMIRISHETTY; Annie RICHHARIA
- Web page: https://patentgrep.com/patent/US20210275502A1

## CPC

- A61K 31/426: 1,3-Thiazoles
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/32: Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone}
- A61P 17/00: Drugs for dermatological disorders
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 277/28: Radicals substituted by nitrogen atoms
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to a process for preparing N-[2-[2-(4-chlorophenyl)-4-thiazolyl] ethyl]-butanamide. The present invention further relates to a pharmaceutical formulation and the use of said pharmaceutical formulation consisting of N-[2-[2-(4-chlorophenyl) -4-thiazolyl]ethyl]-butanamide or pharmaceutically acceptable salts thereof as active compound for the treatment and prevention of autoimmune diseases and diseases involving skin immunology, skin autoimmune diseases and pigmentation disorders.

## Claims

### Claim 1

A process for preparing N-[2-[2-(4-Chlorophenyl)-4-thiazolyl]ethyl]-butanamide, comprising the steps of:
a. refluxing 4-chlorobenzathiomide with a suitable reagent for esterification to obtain an ester;
b. reducing the ester to obtain a reduced intermediate;
c. reacting the reduced intermediate (alcohol or aldehyde) with a suitable reagent to obtain a thiazole:
d. optionally reducing the intermediate with a reducing agent or reacting the said intermediate with a suitable reagent to obtain [2-[2-(4-chlorophenyl)-4-thiazolyl] ethyl]-butanamide.

### Claim 2 (depends on 1)

The process as claimed in claim 1, comprising the steps of:
(1) Refluxing 4-chlorobenzathiomide with the adding chloroacetoacetate to obtain Ethyl 2-(2-(4-chlorophenyl)thiazol-4-yl)acetate;
(2) Reducing ethyl 2-(2-(4-chlorophenyl)thiazol-4-yl)acetate with the addition of sodium borohydride to obtain 2-(2-(4-chlorophenyl)thiazol-4-yl)ethan-1-ol;
(3) Reacting 2-(2-(4-chlorophenyl)thiazol-4-yl)ethan-1-ol as obtained in step (2) with methylsulphonyl chloride and then with NaN3 to obtain 4-(2-azidoethyl)-2-(4-chlorophenyl) thiazole; and
(4) Reducing 4-(2-azidoethyl)-2-(4-chlorophenyl) thiazole as obtained in step (4) with triphenyl phosphine to obtain [2-[2-(4-chlorophenyl)-4-thiazolyl]ethyl]-butanamide.

### Claim 3 (depends on 1)

The process as claimed in claim 1 comprising the steps of:
(1) Refluxing 4-chlorobenzathiomide adding Ethyl 3-bromo-2-oxopropanoate to obtain Ethyl 2-(2-(4-chlorophenyl)thiazol-4-yl)acetate;
(2) Reducing ethyl 2-(2-(4-chlorophenyl)thiazol-4-yl)acetate as obtained in step (1) with the addition of DIBAL-H solution to obtain 2-(4-chlorophenyl)thiazole-4-carbaldehyde;
(3) Reacting 2-(4-chlorophenyl)thiazole-4-carbaldehyde as obtained in step (2) was then reacted with nitromethane, pyrrolidine and acetic acid respectively;
(4) Reducing the 2-(4-chlorophenyl)-4-(2-nitrovinyl) thiazole obtained from step (3) with Pd to obtain -(4-chlorophenyl)thiazole-4-yl)ethane-1-aminen;
(5) Reacting 2-(4-chlorophenyl)thiazole-4-yl)ethane-1-aminen as obtained in step (4) with triethyl amine and further with butyryl chloride to obtain [2-[2-(4-chlorophenyl)-4-thiazolyl]ethyl]-butanamide.

### Claim 4

A pharmaceutical formulation comprising N-[2-[2-(4-chlorophenyl)-4-thiazolyl]ethyl]-butanamide or pharmaceutically acceptable salts thereof as the active compound and a pharmaceutically acceptable excipient, wherein the strength of the active compound is in the range of 0.1% to 90%.

### Claim 5 (depends on 4)

The pharmaceutical formulation as claimed in claim 4, wherein the strength of the active compound or pharmaceutically acceptable salts thereof, is in the range of 0.1% to 20%.

### Claim 6 (depends on 4)

The pharmaceutical formulation as claimed in claim 4, wherein the formulation is for topical application and comprises N-[2-[2-(4-chlorophenyl)-4-thiazolyl]ethyl]-butanamide or pharmaceutically acceptable salts thereof, in the range of 0.1 to 40 wt %, dissolved in a solvent added in an amount in the range of 8-25 wt %, along with a gelling agent in an amount in the range of 45-65 wt % and a permeation enhancer which is in an amount in the range of 10-25 wt %.

### Claim 7 (depends on 6)

The pharmaceutical formulation as claimed in claim 6, optionally comprising a stiffening agent, emulsifying agent, gelling agent, humectant, preservative, antioxidant, chelating agent, buffer and a suitable solvent.

### Claim 8 (depends on 6)

The pharmaceutical formulation as claimed in claim 6, wherein the solvent is selected from the group consisting of purified water, hexylene glycol, propylene glycol, oleyl alcohol and propylene carbonate.

### Claim 9 (depends on 6)

The pharmaceutical formulation as claimed in claim 6, wherein the gelling agent is selected from the group consisting of carbomer, methyl cellulose, sodium carboxyl methyl cellulose, carrageenan, colloidal silicon dioxide, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelatin, polyethylene oxide, alginic acid and Sodium alginate.

### Claim 10 (depends on 6)

The pharmaceutical formulation as claimed in claim 6, wherein the permeation enhancer is selected from the group consisting of propylene glycol, ethanol, isopropyl alcohol, oleic acid and polyethylene glycol.

### Claim 11 (depends on 4)

The formulation as claimed in claim 4, for use as a medicament for the treatment of skin autoimmune diseases and pigmentation disorders including but not limited to Vitiligo, Psoriasis, Atopic dermatitis and eczema, lichen-planus, Scleroderma, Pemphigus, Bullous, Epidermolysis bullosa, Systemic lupus erythematosus, dermatomyositis, and Alopecia areata.

### Claim 12 (depends on 11)

The formulation as claimed in claim 11, for use as a medicament for the treatment of vitiligo.

### Claim 13 (depends on 4)

The formulation as claimed in claim 4, administered by way of oral, parenteral, topical, transdermal, intravenous, rectal, sublingual, nasal, rectal, and local administration.

### Claim 14 (depends on 4)

The formulation as claimed in claim 4, in the dosage form of a solution, gel, ointment, cream, lotion, spray or foam.

### Claim 15

A method for the treatment of autoimmune diseases in a mammal diagnosed with the disease, the method comprising the step of administering to the mammal a therapeutically effective amount of N-[2-[2-(4-chlorophenyl)-4-thiazolyl]ethyl]-butanamide or pharmaceutically acceptable salts thereof.

### Claim 16 (depends on 15)

The method as claimed in claim 15, wherein the subject is identified as being at risk of developing a skin autoimmune disease selected from the group consisting of vitiligo, psoriasis, atopic dermatitis, eczema, lichen-planus, scleroderma, pemphigus, bullous, epidermolysis bullosa, systemic lupus erythematosus, dermatomyositis, and alopecia areata.

### Claim 17 (depends on 15)

The method as claimed in claim 15, wherein the subject has one or more depigmented skin areas, and the compound is applied topically to at least one of the depigmented skin areas.

### Claim 18 (depends on 15)

The method for the treatment of autoimmune diseases as claimed in claim 15, wherein the treatment includes prophylactic and therapeutic treatments.

### Claim 19 (depends on 15)

The method as claimed in claim 15, wherein the compound is administered either in combination or adjunctively with a second therapeutic treatment or active agent.