[기초재료화학기술]Pfizer, Inc./ UCB Pharma GMBH 대 Mylan Pharmaceuticals, Inc. 간의 기초재료화학기술 관련 특허 분쟁

발생일자 2015.01.27

사건번호 1:15-cv-00013

법원국가 UNITED STATES OF AMERICA

관할법원명 D.C.N.D.WestVirginia(지방법원)

침해권리 특허

원고명 Pfizer, Inc./ UCB Pharma GMBH ( 미국 / 외국기업 )

피고명 Mylan Pharmaceuticals, Inc. ( 미국 / 외국기업 )

소송유형 침해금지

분쟁내용

[Pfizer, Inc. et al v. Mylan Pharmaceuticals, Inc.] 사건번호 1:15-cv-00013에 따르면 원고 Pfizer, Inc./ UCB Pharma GMBH는 피고 Mylan Pharmaceuticals, Inc.을 상대로 특허 US6858650, US7384980, US7855230, US7985772, US8338478 을 침해하였다는 이유로 미국 웨스트버지니아 북부 지방법원에 소를 제기하였다.

분쟁결과 분쟁중

산업분류 화학∙바이오 > 기초재료화학기술

계쟁제품 Fesoterodine fumarate extended release tablets, generic version of Toviaz

지재권번호/명칭

US6858650 Stable salts of novel derivatives of 3,3-diphenylpropylamines

US7384980 Derivatives of 3,3-diphenylpropylamines

US7855230 Derivatives of 3,3-diphenylpropylamines

US7985772 Derivatives of 3,3-diphenylpropylamines

US8338478 Derivatives of 3,3-diphenylpropylamines

Stable salts of novel derivatives of 3,3-diphenylpropylamines

Abstract

The present invention concerns highly pure, crystalline, stable compounds of novel derivatives of 3,3-diphenylpropylamines in the form of their salts, a method for the manufacture and highly pure, stable intermediate products. The method is in particular characterized by regio- and chemoselectivity and high yield. Salts of phenolic monoesters of 3,3-diphenylpropylamines are provided, that are particularly well-suited for use in pharmaceutical formulations. Preferred compounds are R-(+)-2-(3-diisopropylamino-1-phenyl-propyl)-4-hydroxymethylphenylisobutyr ate ester hydrogen fumarate and R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyra te ester hydrochloride hydrate. Furthermore, stable, crystalline intermediate products that are essential for obtaining the abovementioned salts are provided. A preferred intermediate product is R-(-)-3-(3-diisopropylamino-phenyl-propyl)-4-hydroxy-benzoic acid methyl ester.

Claims

What is claimed is:

1. Compounds of general formula I ##STR35##

in which R denotes C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.10 -cycloalkyl, substituted or unsubstituted phenyl and X.sup.- is the acid residue of a physiologically compatible inorganic or organic acid.

2. Compounds in accordance with claim 1, characterised in that X.sup.- in each case is an acid ester of hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, stearic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, DL-malic acid, L-(-)-malic acid, D-(+)-malic acid, DL-tartaric acid, L-(+) -tartaric acid, D-(-)-tartaric acid, citric acid, L-aspartic acid, L-(+)-ascorbic acid, D-(+)-glucuronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid (mucic acid), benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, vanillic acid, 4-hydroxycinammic acid, gallic acid, hippuric acid (N-benzoyl-glycine), aceturic acid (N-aectylglycine), phloretinic acid (3-(4-hydroxyphenyl)-propionic acid), phthalic acid, methanesulfonic acid or orotic acid.

3. Compounds in accordance with claims 1, characterised in that they have general formula 2: ##STR36##

in which R denotes C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.10 -cycloalkyl, substituted or unsubstituted phenyl and X.sup.- is the acid residue of a physiologically compatible inorganic or organic acid.

4. Compounds in accordance with claim 3, characterised in that X in each case is an acid ester of hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, stearic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, DL-malic acid, L-(-)-malic acid, D-(+)-malic acid, DL-tartaric acid, L-(+)-tartaric acid, D-(-)-tartaric acid, citric acid, L-aspartic acid, L-(+)-ascorbic acid, D-(+)-glucuronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid (mucic acid), benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, vanillic acid, 4-hydroxycinammic acid, gallic acid, hippuric acid (N-benzoyl-glycine), aceturic acid (N-aectylglycine), phloretinic acid (3-(4-hydroxyphenyl)-propionic acid), phthalic acid, methanesulfonic acid or orotic acid.

5. Compounds in accordance with claims 3, characterised in that they are R-(+)-2-(3-(diisopropylamino-1-phenylpropyl)-4-hydroxymethyl -phenylisobutyrate ester hydrogen fumarate, R-(+)-2-(3-(diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyr ate ester-hydrochloride hydrate.

6. Compounds in accordance with claims 3, characterised in that R stands for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-(1-cyclopropyl-methanoyloxy)-phenyl, 4-(1-cyclobutyl-methanoyloxy)-phenyl, 4-(1-cyclohexyl-methanoyloxy)-phenyl or 4-(2,2-dimethyl-propanoyloxy)-phenyl and X.sup.- denotes chloride.

7. Method for manufacturing compounds of general formula I ##STR37##

in which R denotes C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.10 -cycloalkyl, substituted or unsubstituted phenyl and X- is the acid residue of a physicologically compatible inorganic or organic acid, characterised in that a) a compound of formula III ##STR38##

is split with a hydrogenation agent to form a compound of Formula V ##STR39##

whereupon b) the compoud of formula V so obtained is converted with a reducing agent, in order to give a compound of formula VI ##STR40##

which c) is converted with an acylation agent, in order to obtain a compound of formula A ##STR41##

in which R has the significance stated above, which d) is converted with a physiologically compatible inorganic or organic acid to form a compound of formula I ##STR42##

in which R denotes C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.10 -cycloalkyl, unsubstituted or substituted phenyl and X- is the acid residue of a physiologically compatible inorganic or organic acid.

8. Method in accordance with claim 7, characterised in that for the manufacture of the compounds of general formula I hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, stearic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, DL-malic acid, L-(-)-malic acid, D-(+)-malic acid, DL-tartaric acid, L-(+)-tartaric acid, D-(-)-tartaric acid, citric acid, L-aspartic acid, L-(+)-ascorbic acid, D-(+)-glucuronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid (mucic acid), benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, vanillic acid, 4-hydroxycinammic acid, gallic acid, hippuric acid (N-benzoyl-glycine), aceturic acid (N-aectylglycine), phloretinic acid (3-(4-hydroxyphenyl)-propionic acid), phthalic acid, methanesulfonic acid or orotic acid are used.

9. Method for manufacturing compounds of general formula 2 ##STR43##

in which R denotes C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.10 -cycloalkyl, substituted or unsubstituted phenyl and X- is the acid residue of a physiologically compatible inorganic or organic acid, characterised in that a) a compound of the formula 3 ##STR44##

s split with a hydrogenation agent to form a compound of formula 5 ##STR45##

whereupon b) the compound formula 5 so obtained is converted with a reducing agent, in order to give a compound of formula 6 ##STR46##

which c) is converted with an acylation agent, in order to obtain a compound of formula 1 ##STR47##

in which R has the significance stated above, which d) is converted with a physiologically compatible inorganic or organic acid to form a compound of formula 2 ##STR48##

in which R denotes C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.10 -cycloalkyl, unsubstituted or substituted phenyl and X- is the acid residue of a physiologically compatible inorganic or organic acid.

10. Method in accordance with claim 9, characterised in that for the manufacture of the compounds of general formula 2 hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, stearic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, DL-malic acid, L-(-)-malic acid, D-(+)-malic acid, DL-tartaric acid, L-(+)-tartaric acid, D-(-)-tartaric acid, citric acid, L-aspartic acid, L-(+)-ascorbic acid, D-(+)-glucuronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid (mucic acid), benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, vanillic acid, 4-hydroxycinammic acid, gallic acid, hippuric acid (N-benzoyl-glycine), aceturic acid (N-aectylglycine), phloretinic acid (3-(4-hydroxyphenyl)-propionic acid), phthalic acid, methanesulfonic acid or orotic acid are used.

11. Method in accordance with claims 7, characterised in that as the hydrogenation agent, Raney nickel/H.sub.2 in methanol is preferably used as the solvent.

12. Method in accordance with claims 7, characterised in that for the reducing agent NaBH.sub.4 EtOH, preferably LiAlH.sub.4 /THF, is used.

13. Method in accordance with claims 7, characterised in that for the acylation agent isobutyrylchloride and for the base triethylamine are used.

14. Method in accordance with claims 9, characterised in that a compound of general formula 6 is converted with an equivalent isobutyryl chloride in the presence of triethylamine using one of the respective solvents ethylacetate, dichloromethane, tetrahydrofurane, acetonitrile or toluene regio- and chemoselectively into R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyra te.

15. Method in accordance with claims 9, characterised in that R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyra te ester and fumaric acid or hydrochloric acid are converted with the formation of the respective salt.

16. Method in accordance with claims 9 for the manufacture of R-(+)-2-(3-diisopropylamino-1-phenyl-propyl)-4-hydroxy-methylphenylisobuty rate ester hydrochloride hydrate, characterised in that the phenolic esterification of R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxy-methylphenol (6) is carried out without the addition of an external base, in that solutions of (6) are dropped into solutions of isobutyryl chloride, that contain at least 1 mole equivalent of water, in order to directly obtain a corresponding stable, hydrate-containing hydrochloride.

17. Compound of formula 7 ##STR49##

18. A method of manufacture of phenolic monoesters of general formula 1 ##STR50##

wherein the method comprises the steps of: providing a compound of claim 17; deprotecting the hydroxyl residues of the 4-hydroxy-benzyl alcohol residue; and acylating the phenol residue.

19. A method of manufacture of salts of phenolic monoesters of general formula 2: ##STR51##

in which R denotes C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.10 -cycloalkyl, substituted or unsubstituted phenyl and X.sup.- is the acid residue of a physicologically compatible inorganic or organic acid, wherein the method comprises the steps of: providing a compound of claim 17; deprotecting the hydroxyl residues of the 4-hydroxy-benzyl alcohol residue; and acylating the phenol residue.

20. A method of manufacture of R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyra te ester hydrogen fumarate or R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyra te ester hydrochloride hydrate, the method comprising the steps of; providing a compound of claim 17; deprotecting the hydroxyl residues of the 4-hydroxy-benzyl alcohol residue; and acylating the phenol residue.

21. A method of treating a patient suffering from urinary incontinence, which method comprises the step of administering to said patient an effective amount of a compound according to claim 1.

22. A method of treating a patient suffering from urinary incontinence, which method comprises the step of administering to said patient an effective amount of a compound according to claim 3.

23. A method of treating a patient suffering from urinary incontinence, which method comprises the step of administering to said patient an effective amount of a compound according to claim 5.

24. The method of any one of claims 21-23, wherein the urinary incontinence disorder is urge incontinence.

Derivatives of 3,3-diphenylpropylamines

Abstract

The invention concerns novel derivatives of 3,3-diphenylpropylamines, methods for their preparation, pharmaceutical compositions containing the novel compounds, and the use of the compounds for preparing drugs. More particularly, the invention relates to novel prodrugs of antimuscarinic agents with superior pharmacokinetic properties compared to existing drugs such as oxybutynin and tolterodine, methods for their preparation, pharmaceutical compositions containing them, a method of using said compounds and compositions for the treatment of urinary incontinence, gastrointestinal hyperactivity (irritable bowel syndrome) and other smooth muscle contractile conditions.

Claims

The invention claimed is:

1. R-(+)-isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester.

2. A salt of R-(+)-isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester with a physiologically acceptable acid.

3. A pharmaceutical composition comprising an effective amount of R-(+)-isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, or a salt thereof with a physiologically acceptable acid and a pharmaceutically acceptable carrier.

4. A method of antagonizing a muscarinic receptor in a patient in need thereof, the method comprising administering to the patient R-(+)-isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester or a salt thereof with a physiologically acceptable acid so as to result in contact of the muscarinic receptor with an effective amount of R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol.

5. A method of treating a disease in a mammal that is amenable to treatment by antagonizing muscarinic receptors in the mammal, the method comprising administering to the mammal a pharmaceutical composition comprising an effective amount of R-(+)-isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester or a salt thereof with a physiologically acceptable acid.

6. The method according to claim 5 wherein the disease is urinary incontinence.

7. The method according to claim 6 wherein the mammal is a human.

8. A compound selected from the group consisting of: acetic acid 4-acetoxy-3-(3-diisopropylamino- 1-phenylpropyl)-benzyl ester, n-butyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-isobutyryloxymethylphenyl ester, n-butyric acid 4-n-butyryloxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester, propionic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-propionyloxymethylphenyl ester, propionic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, and acetic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, including racemic mixtures and individual enantiomers of said compounds, and salts of said compounds with a physiologically acceptable acid.

9. The compound of claim 8 where the compound is selected from the group consisting of: n-butyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, propionic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, and acetic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, including racemic mixtures and individual enantiomers of said compounds, and salts of said compounds with a physiologically acceptable acid.

10. A pharmaceutical composition comprising an effective amount of a compound selected from the group consisting of: acetic acid 4-acetoxy-3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester, n-butyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-isobutyryloxymethylphenyl ester, n-butyric acid 4-n-butyryloxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester, propionic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-propionyloxymethylphenyl ester, propionic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, and acetic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, including racemic mixtures and individual enantiomers of said compounds, and salts of said compounds with a physiologically acceptable acid, and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10 where the compound is selected from the group consisting of: n-butyric acid 2-(3-diisopropylamino-1a-phenylpropyl)-4-hydroxymethylphenyl ester, isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, propionic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, and acetic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, including racemic mixtures and individual enantiomers of said compounds, and salts of said compounds with a physiologically acceptable acid.

12. A method of treating a disease or condition in a mammal that is amenable to treatment by antagonizing muscarinic receptors in the mammal, the method comprising administering to the mammal a pharmaceutical composition comprising an effective amount of a compound selected from the group consisting of: acetic acid 4-acetoxy-3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester, n-butyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-isobutyryloxymethylphenyl ester, n-butyric acid 4-n-butyryloxymethyl-2-(3-diisopropylamino- 1-phenylpropyl)-phenyl ester, propionic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-propionyloxymethylphenyl ester, propionic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, and acetic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, including racemic mixtures and individual enantiomers of said compounds, and salts of said compounds with a physiologically acceptable acid.

13. The method of claim 12 where the compound is selected from the group consisting of: n-butyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, propionic acid 2-(3-.diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, and acetic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, including racemic mixtures and individual enantiomers of said compounds, and salts of said compounds with a physiologically acceptable acid.

14. The method of claim 12 or 13 where the disease or condition is a spasmogenic condition that is caused by a muscarinic mechanism.

15. The method of claim 12 or 13 where the disease or condition is urinary incontinence.

16. The method of claim 15 where the mammal is a human.

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