# US 8,569,489 B2 · 7-[4-(Benzhydrylpiperazinyl-1)butyl]-3-methylxanthine and its salts with organic or inorganic acids possessing antihistaminic and antiallergenic activity

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- Number: US 8,569,489 B2
- Document ID: US8569489B2
- Status: Granted
- Kind: B2
- Application number: 12/568,880
- Filed: 2009-09-29
- Published: 2010-07-01
- Granted: 2013-10-29
- Earliest claimed: 2007-03-29
- Assignees: A.B. Intelpharm Limited
- Applicants: Robert G. Glushkov; Sergei D. Juzhakov; Olga S. Fominova; Nelli M. Sazonova; Elena M. Dolginova; Vadim A. Shorr; Mikhail V. Borovkov; Valentina V. Asnina
- Inventors: Robert G. Glushkov; Sergei D. Juzhakov; Olga S. Fominova; Nelli M. Sazonova; Elena M. Dolginova; Vadim A. Shorr; Mikhail V. Borovkov; Valentina V. Asnina
- Web page: https://patentgrep.com/patent/US8569489B2

## CPC

- C07D 473/06: with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- A61P 27/14: Decongestants or antiallergics
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to a range of original xanthine derivatives substituted in 1 -and 7-positions with benzhydryl-4-piperazinyl-1-alkane fragments. A method for obtaining 3-methyl-7-[4-(benzhydryl-4-piperazinyl-1)butyl]xanthine and the salts thereof with organic and inorganic acids by alkylating the 7-potassium salt of 3-methylxanthine by 1,4-dibromobutane, by subsequently interacting the thus formed 7-(4-bromobutyl)-3-methylxanthine with 1-benzhydrylpiperazinyl and by neutralising the thus obtained radical 7-/4-(4-benzhydrylpiperazinyl-1) butyl/-3-methylxanthine by an organic or inorganic acid is also disclosed.

## Claims

### Claim 1

7-[4-(benzhydrylpiperazinyl-1)butyl]-3-methylxanthine dihydrochloride capable of producing an antihistaminic and antiallergenic effect:
wherein R is H; wherein R1 is Me; wherein n =2; wherein X is H; and wherein Y is H and Y1 is H.

### Claim 2

7-[4-(benzhydrylpiperazinyl-1)butyl]-3-methylxanthine or a pharmaceutically acceptable salt or hydrate thereof, capable of producing an antihistaminic and antiallergenic effect, of formula II:
wherein R is H and R1 is Me; wherein n =2; wherein X is H; and wherein Y is H and Y1 is H.

### Claim 3

7-[4-(benzhydrylpiperazinyl-1)butyl]-3-methylxanthine oxalate, capable of producing an antihistaminic and antiallergenic effect, of formula II:
wherein R is H and R1 is Me; wherein n =2; wherein X is H; wherein Y is H and Y1 is H; and the compound as an oxalate salt.

### Claim 4

7-[4-(benzhydrylpiperazinyl-1)butyl]-3-methylxanthine succinate, capable of producing an antihistaminic and antiallergenic effect, of formula II:
wherein R is H and R1 is Me; wherein n =2; wherein X is H; wherein Y is H and Y1 is H; and the compound as a succinate salt.

### Claim 5

A compound 7-[4-(benzhydrylpiperazinyl-1)butyl]-3-methylxanthine of formula:
made by a process comprising:
alkylating the 7-potassium salt of 3-methylxanthine with 1,4-dibromobutane to produce 7-(4-bromobutyl)-3-methylxanthine, and reacting the 7-(4-bromobutyl)-3-methylxanthine with 1-benzhydrylpiperazine to produce 7-[4-(4-benzhydryl-piperazinyl-1)butyl]-3-methylxanthine.

### Claim 6 (depends on 5)

The compound according to claim 5, wherein alkylating the 7-potassium salt of 3-methylxanthine with the 1,4-dibrombutane, as well as reacting the 7-(4-bromobutyl)-3-methylxanthine with the 1-benzhydrylxanthine takes place in an organic solvent.

### Claim 7 (depends on 5)

The compound according to claim 5, wherein reacting the 7-(4-bromobutyl)-3-methylxanthine with the 1-benzhydrylpiperazine takes place in the presence of an organic base.

### Claim 8 (depends on 6)

The compound according to claim 6, wherein the organic solvent is acetonitrile.

### Claim 9 (depends on 6)

The compound according to claim 6, wherein reacting the 7-(4-bromobutyl)-3-methylxanthine with the 1-benzhydrylpiperazine takes place in the presence of an organic base.

### Claim 10 (depends on 9)

The compound according to claim 9, wherein the organic base is triethylamine.

### Claim 11

A method of producing 7-[4-(benzhydryl-4-piperazinyl-1)butyl]-3-methylxanthine of formula:
comprising:
alkylating the 7-potassium salt of 3-methylxanthine with 1,4-dibromobutane to produce 7-(4-bromobutyl)-3-methylxanthine, wherein alkylating the 7-potassium salt of 3-methylxanthine takes place with a four-fold molar excess of 1,4-dibromobutane; and reacting the 7-(4-bromobutyl)- 3-methylxanthine with 1-benzhydrylpiperazine to produce 7-[4-(4-benzhydryl-piperazinyl-1)butyl]-3-methylxanthine.

### Claim 12 (depends on 11)

The method according to claim 11, wherein alkylating the 7-potassium salt of 3-methylxanthine takes place with the four-fold molar excess of the 1,4-dibromobutane takes place in an organic solvent; and reacting the 7-(4-bromobutyl)-3-methylxanthine with the 1-benzhydrylxanthine takes place in the organic solvent.

### Claim 13 (depends on 11)

The method according to claim 11, wherein reacting the 7-(4-bromobutyl) -3-methylxanthine with the 1-benzhydrylpiperazine takes place in the presence of an organic base.

### Claim 14 (depends on 12)

The method according to claim 12, wherein the organic solvent is acetonitrile.

### Claim 15 (depends on 12)

The method according to claim 12, wherein reacting the 7-(4-bromobutyl) -3-methylxanthine with the 1-benzhydrylpiperazine takes place in the presence of an organic base.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the organic base is triethylamine.

### Claim 17

A method of producing a salt of 7-[4-(benzhydryl-piperazinyl-1)butyl]-3-methylxanthine of formula XI:
where HX is an organic acid or inorganic acid, comprising:
alkylating the 7-potassium salt of 3-methylxanthine with a four-fold molar excess of 1,4-dibromobutane to produce 7-(4-bromobutyl)-3-methylxanthine; reacting the 7-(4-bromobutyl)- 3-methylxanthine with 1-benzhydrylpiperazine to produce 7-[4-(4-benzhydryl-piperazinyl-1)butyl]-3-methylxanthine; and neutralizing the 7-[4-(4-benzhydryl-piperazinyl-1)butyl]-3-methylxanthine with the organic or inorganic acid to form the salt.

### Claim 18

A pharmacotherapeutic method for treating an allergic illness in a patient by administering to the patient an antihistamine dosage form, comprising: administering an effective amount of a compound 7-[4-(benzylhydrylpiperazinyl-1)butyl]-3-methylxanthine or a pharmaceutically acceptable salt or hydrate thereof in a dosage form, the antihistaminic dosage form capable of producing an antihistaminic effect in the patient to treat an allergic illness in the patient.

### Claim 19 (depends on 18)

The method of claim 18, wherein the dosage form is selected from the group consisting of an oral form, an intravenous form, an eye drop form, and a solid drug dose form.

### Claim 20 (depends on 18)

The method according to claim 18, wherein the dosage form is capable of administering between about 1 mg to about 3 mg of the compound 7-[4-(benzylhydrylpiperazinyl-1)butyl]-3-methylxanthine or a pharmaceutically acceptable salt or hydrate thereof to the patient per each kilogram of body weight of the patient.