JP2007537187A - Hydroxy-substituted benzofused heterocyclic compounds for use as beta agonists in the treatment of respiratory diseases - Google Patents

Abstract

の化合物（式中、ｎ、Ａ、Ｂ、Ｒ¹、Ｒ²及びＲ³は、請求項及び明細書において定義されるようなものである）、及び同一物を製造するための方法に関する。本発明は、また、薬剤としての、特には、呼吸器疾患の治療において使用するための薬剤としてのこれらの化合物の使用に関する。The present invention relates to a general formula (1):
[Chemical 1]

Wherein n, A, B, R ¹ , R ² and R ³ are as defined in the claims and specification, and a process for preparing the same. The invention also relates to the use of these compounds as medicaments, in particular as medicaments for use in the treatment of respiratory diseases.

Description

Detailed Description of the Invention

（式中の基ｎ、Ａ、Ｂ、Ｒ¹、Ｒ²及びＲ³は、請求項及び明細書に記載の意味を有していてもよい）の化合物、それらを製造する方法、及び医薬組成物としての、特には、呼吸器疾患(complaint)の治療用医薬組成物としてのそれらの使用に関する。 The present invention is directed to general formula 1:

Compounds in which the groups n, A, B, R ¹ , R ² and R ³ may have the meanings given in the claims and the specification, the process for producing them and the pharmaceutical composition It relates to their use as pharmaceuticals, in particular as pharmaceutical compositions for the treatment of respiratory complaints.

Background of the Invention Betamimetics (β-adrenergic substances) are known in the art. For example, reference is made in connection with the disclosure of US 4,460,581, which proposes beta mimetics for the treatment of various diseases.
For drug treatment of diseases, it is often desirable to produce a medicament with long-term activity. In general, this ensures that the concentration of the active substance in the body that is required to achieve a therapeutic action is guaranteed for a long time without the need to re-administer the drug frequently. Furthermore, providing the active substance at longer intervals contributes to the patient's health to a high degree. It is particularly desirable to produce a pharmaceutical composition that can be used therapeutically by administration once a day (single administration). The use of the drug once a day has the advantage that the patient can become accustomed to taking the drug regularly at certain times of the day.
The object of the present invention is therefore on the one hand to provide therapeutic benefits in the treatment of respiratory diseases and also to be characterized by long-term activity and therefore to be used to produce pharmaceutical compositions having long-term activity. It is to provide possible beta mimetics. A detailed object of the present invention is to produce beta mimetics that can be used for using once a day drugs to treat respiratory diseases because of their long lasting action That is. Apart from the above, a further object of the present invention is to produce beta mimetics that are not only very powerful, but also characterized by a high degree of selectivity with respect to the β ₂ -adrenoceptor.

Detailed Description of the Invention It has surprisingly been found that these objects are achieved with compounds of the general formula 1.
Thus, the present invention may optionally be in the form of individual enantiomers, individual enantiomers or racemic mixtures, and optionally in the form of acid addition salts with pharmacologically acceptable acids. And optionally compounds of general formula 1 which may be in the form of their solvates and / or hydrates:

Wherein n is 1 or 2, preferably 1;
A is a double-bonded group selected from — (C═O) —, —S (═O) —, —S (═O) ₂ —, and —C (R ⁴ R ⁵ ) —. Indicates;
B represents —O—, —NR ⁶ , —CH ₂ —, —S—CR ⁷ R ⁸ —, —NR ⁶ —CR ⁷ R ⁸ —, —CH ₂ —CR ⁷ R ⁸ —, —O—CR ^9. R ¹⁰ - and denotes a double-bonded group selected from -CH = CH-;
R ¹ and R ² may be the same or different and represent hydrogen, C _1-4 alkyl, halogen, OH or —O—C _1-4 alkyl;
R ³ is hydrogen, C _1-4 alkyl, OH, halogen, —O—C _1-4 alkyl, —COOH, —COO—C _1-4 alkyl, —O—C _1-4 alkylene-COOH or —O. -C _1-4 alkylene-CO-O-C _1-4 alkyl is shown;
R ⁴ and R ⁵ may be the same or different and are hydrogen, C _1-4 alkyl, OH, halogen, —O—C _1-4 alkyl, —COOH or —COO—C _1-4 alkyl. Indicates;
R ⁶ represents hydrogen or C _1-4 alkyl;
R ⁷ and R ⁸ may be the same or different and represent hydrogen or C _1-4 alkyl;
R ⁹ and R ¹⁰ may be the same or different and represent C _1-4 alkyl).

Preferred is
n represents 1 or 2, preferably 1;
A represents a double bond group selected from — (C═O) —, —S (═O) ₂ —, and —C (R ⁴ R ⁵ ) —;
B represents —O—, —NR ⁶ —, —CH ₂ —, —S—CR ⁷ R ⁸ —, —NR ⁶ —CR ⁷ R ⁸ —, —CH ₂ —CR ⁷ R ⁸ —, —O—CR. ⁹ represents a double bond group selected from R ¹⁰ -and -CH = CH-;
R ¹ and R ² may be the same or different and represent hydrogen, methyl, ethyl, propyl, fluorine, chlorine, bromine, OH, methoxy or ethoxy;
R ³ is hydrogen, methyl, ethyl, propyl, fluorine, chlorine, bromine, OH, methoxy, ethoxy, —COOH, —COO methyl, —COO ethyl, —O—CH ₂ —COOH, —O—CH ₂ —COO. - methyl, -O-CH ₂ -COO- _{ethyl, -O-CH 2 -CH 2 -COOH} , -O-CH 2 -CH 2 -COO- methyl, -O-CH ₂ -CH ₂ -COO- ethyl, _{-O-CH 2 -CH 2 -CH 2} -COOH, -O-CH 2 -CH 2 -CH 2 -COO- methyl or _{-O-CH 2 -CH 2 -CH 2} -COO- ethyl;
R ⁴ and R ⁵ may be the same or different and represent hydrogen, methyl, ethyl, OH, fluorine, chlorine, —COOH, —COO methyl or —COO ethyl;
R ⁶ represents hydrogen, methyl, ethyl or propyl, preferably hydrogen;
R ⁷ and R ⁸ may be the same or different and represent hydrogen, methyl, ethyl or propyl;
R ⁹ and R ¹⁰ may be the same or different and represent methyl, ethyl or propyl;
It may optionally be in the form of individual enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, and in some cases A compound of formula 1 which may be in the form of a solvate and / or hydrate of

Also preferred is
n represents 1 or 2, preferably 1;
A represents a double bond group selected from — (C═O) —, —S (═O) ₂ —, and —C (R ⁴ R ⁵ ) —;
B represents —O—, —NR ⁶ —, —CH ₂ —, —S—CR ⁷ R ⁸ —, —NR ⁶ —CR ⁷ R ⁸ —, —CH ₂ —CR ⁷ R ⁸ —, —O—CR. ⁹ represents a double bond group selected from R ¹⁰ -and -CH = CH-;
R ¹ and R ² may be the same or different and represent hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy or ethoxy;
R ³ is hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy, ethoxy, —COOH, —COO methyl, —COO ethyl, —O—CH ₂ —COOH, —O—CH ₂ —COO-methyl, — O-CH ₂ -COO- _{ethyl, -O-CH 2 -CH 2 -COOH} , -O-CH 2 -CH 2 -COO- methyl or -O-CH ₂ -CH ₂ -COO- ethyl;
R ⁴ and R ⁵ may be the same or different and represent hydrogen, methyl, ethyl, —COOH, —COO methyl or —COO ethyl;
R ⁶ represents hydrogen, methyl or ethyl;
R ⁷ and R ⁸ may be the same or different and represent hydrogen, methyl or ethyl, preferably hydrogen or methyl;
R ⁹ and R ¹⁰ may be the same or different and represent methyl or ethyl, preferably methyl,
It may optionally be in the form of individual enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, and in some cases A compound of formula 1 which may be in the form of a solvate and / or hydrate of

Also preferred is
n represents 1 or 2, preferably 1;
A represents a double bond group selected from — (C═O) —, —S (═O) ₂ —, and —C (R ⁴ R ⁵ ) —;
B is, -O -, - NH -, - CH 2 -, - S-CH 2 -, - NH-CH 2 -, - CH 2 -CH 2 -, - O-CR 9 R 10 - and -CH = A double bond group selected from CH-;
R ¹ and R ² may be the same or different and represent hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy or ethoxy;
R ³ is hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy, ethoxy, —COOH, —COO methyl, —COO ethyl, —O—CH ₂ —COOH, —O—CH ₂ —COO-methyl, — O-CH ₂ -COO- _{ethyl, -O-CH 2 -CH 2 -COOH} , -O-CH 2 -CH 2 -COO- methyl or -O-CH ₂ -CH ₂ -COO- ethyl;
R ⁴ and R ⁵ may be the same or different and represent hydrogen, methyl, ethyl, —COOH, —COO methyl or —COO ethyl;
R ⁹ and R ¹⁰ may be the same or different and are preferably the same and represent methyl or ethyl, preferably methyl,
It may optionally be in the form of individual enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, and in some cases A compound of formula 1 which may be in the form of a solvate and / or hydrate of

Also preferred is
n represents 1 or 2, preferably 1;
A represents a double bond group selected from — (C═O) — and —S (═O) ₂ —;
B is, -O -, - NH -, - CH 2 -, - S-CH 2 -, - NH-CH 2 -, - CH 2 -CH 2 -, - O-CR 9 R 10 - and -CH = A double bond group selected from CH-;
R ¹ and R ² may be the same or different and represent hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy or ethoxy;
R ³ is hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy, ethoxy, —COOH, —COO methyl, —COO ethyl, —O—CH ₂ —COOH, —O—CH ₂ —COO-methyl, — O-CH ₂ -COO- _{ethyl, -O-CH 2 -CH 2 -COOH} , -O-CH 2 -CH 2 -COO- methyl or -O-CH ₂ -CH ₂ -COO- ethyl;
R ⁹ and R ¹⁰ may be the same or different and are preferably the same and represent methyl or ethyl, preferably methyl,
It may optionally be in the form of individual enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, and in some cases A compound of formula 1 which may be in the form of a solvate and / or hydrate of

Also preferred is
R ¹ and R ² may be the same or different and represent hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy or ethoxy;
R ³ represents hydrogen,
And the groups n, A and B may have the meanings described above,
It may optionally be in the form of individual enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, and in some cases A compound of formula 1 which may be in the form of a solvate and / or hydrate of
Also preferred is
R ¹ and R ² may be the same or different and represent hydrogen, methyl, fluorine, chlorine or methoxy;
R ³ represents hydrogen, methyl, fluorine, chlorine or methoxy;
And the groups n, A and B may have the meanings described above,
It may optionally be in the form of individual enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, and in some cases A compound of formula 1 which may be in the form of a solvate and / or hydrate of

Also preferred is
R ³ is methyl, ethyl, fluorine, chlorine, OH, methoxy, ethoxy, —COOH, —COO methyl, —COO ethyl, —O—CH ₂ —COOH, —O—CH ₂ —COO-methyl, —O—. CH ₂ -COO- _{ethyl, -O-CH 2 -CH 2 -COOH} , -O-CH 2 -CH 2 -COO- methyl or -O-CH ₂ -CH ₂ -COO- ethyl indicates,
And the groups n, R ¹ , R ² , A, B may have the meanings described above,
It may optionally be in the form of individual enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, and in some cases A compound of formula 1 which may be in the form of a solvate and / or hydrate of
Also preferred is
R ³ is methyl, ethyl, OH, methoxy, ethoxy, —O—CH ₂ —COOH, —O—CH ₂ —COO-methyl or —O—CH ₂ —COO-ethyl, preferably OH, methoxy or ethoxy Indicate
And the groups n, R ¹ , R ² , A, B may have the meanings described above,
It may optionally be in the form of individual enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, and in some cases A compound of formula 1 which may be in the form of a solvate and / or hydrate of

により特徴付けられる。
好ましい態様においては、本発明は、式１ａの化合物に関し、式中、ｎ、Ｒ¹、Ｒ²及びＲ³は、上記に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。 A compound of formula 1 wherein A represents — (C═O) — and B represents —CH═CH— is represented by the general formula 1a:

Is characterized by
In a preferred embodiment, the invention relates to compounds of formula 1a, in which n, R ¹ , R ² and R ³ may have the meanings indicated above, They may be in the form of enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, and in some cases their solvates. And / or in the form of hydrates.

により特徴付けられる。
好ましい態様においては、本発明は、式１ｂの化合物に関し、式中、ｎ、Ｒ¹、Ｒ²及びＲ³は、上記に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。 A compound of formula 1 wherein A represents — (C═O) — and B represents —CH ₂ —CH ₂ — is represented by the general formula 1b:

Is characterized by
In a preferred embodiment, the invention relates to compounds of formula 1b, in which n, R ¹ , R ² and R ³ may have the meanings indicated above, They may be in the form of enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, and in some cases their solvates. And / or in the form of hydrates.

により特徴付けられる。
好ましい態様においては、本発明は、式１ｃの化合物に関し、式中、ｎ、Ｒ¹、Ｒ²及びＲ³は、上記に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。 Preferred regioisomers of compounds of formula 1 wherein A represents — (C═O) — and B represents —C (methyl) ₂ —O— are represented by the general formula 1c:

Is characterized by
In a preferred embodiment, the invention relates to compounds of formula 1c, in which n, R ¹ , R ² and R ³ may have the meanings indicated above, They may be in the form of enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, and in some cases their solvates. And / or in the form of hydrates.

により特徴付けられる。
好ましい態様においては、本発明は、式１ｄの化合物に関し、式中、ｎ、Ｒ¹、Ｒ²及びＲ³は、上記に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。 Preferred regioisomers of compounds of formula 1 wherein A represents — (C═O) — and B represents —CH ₂ —NH— are represented by the general formula 1d:

Is characterized by
In a preferred embodiment, the invention relates to compounds of formula 1d, in which n, R ¹ , R ² and R ³ may have the meanings indicated above, It may be in the form of enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, and in some cases their solvates. And / or in the form of hydrates.

により特徴付けられる。
好ましい態様においては、本発明は、式１ｅの化合物に関し、式中、ｎ、Ｒ¹、Ｒ²及びＲ³は、上記に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。 Preferred regioisomers of compounds of formula 1 wherein A represents — (C═O) — and B represents —CH ₂ —S— have the general formula 1e:

Is characterized by
In a preferred embodiment, the invention relates to compounds of formula 1e, in which n, R ¹ , R ² and R ³ may have the meanings indicated above, They may be in the form of enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, and in some cases their solvates. And / or in the form of hydrates.

により特徴付けられる。
好ましい態様においては、本発明は、式１ｇの化合物に関し、式中、ｎ、Ｒ¹、Ｒ²及びＲ³は、上記に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。 A compound of formula 1 wherein A represents — (C═O) — and B represents —NH— has the general formula 1g:

Is characterized by
In a preferred embodiment, the invention relates to compounds of formula 1g, in which n, R ¹ , R ² and R ³ may have the meanings indicated above, They may be in the form of enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, and in some cases their solvates. And / or in the form of hydrates.

により特徴付けられる。
好ましい態様においては、本発明は、式１ｈの化合物に関し、式中、ｎ、Ｒ¹、Ｒ²及びＲ³は、上記に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。 A compound of formula 1 wherein A represents — (C═O) — and B represents —O— has the general formula 1h:

Is characterized by
In a preferred embodiment, the invention relates to compounds of formula 1h, in which n, R ¹ , R ² and R ³ may have the meanings indicated above, They may be in the form of enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, and in some cases their solvates. And / or in the form of hydrates.

により特徴付けられる。
好ましい態様においては、本発明は、式１ｉの化合物に関し、式中、ｎ、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴及びＲ⁵は、上に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。
好ましい化合物は、Ｒ⁴が水素を示し、及び、Ｒ⁵が上に記載した意味の１つを有していてもよい式１ｉの化合物であり、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。 A compound of formula 1 wherein A represents —CR ⁴ R ⁵ — and B represents —CH ₂ — is represented by the general formula 1i:

Is characterized by
In a preferred embodiment, the invention relates to compounds of formula 1i, in which n, R ¹ , R ² , R ³ , R ⁴ and R ⁵ may have the meanings indicated above, May optionally be in the form of individual enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, and May be in the form of their solvates and / or hydrates.
Preferred compounds are compounds of formula 1i, wherein R ⁴ represents hydrogen and R ⁵ may have one of the meanings described above, wherein the compounds are optionally individual enantiomers, individual enantiomers Or in the form of a racemic mixture, optionally in the form of an acid addition salt with a pharmacologically acceptable acid, and optionally in the form of solvates and / or hydrates thereof. It may be in the form of a thing.

により特徴付けられる。
好ましい態様においては、本発明は、式１ｊの化合物に関し、式中、ｎ、Ｒ¹、Ｒ²及びＲ³は、上に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。 Preferred regioisomers of compounds of formula 1 wherein A represents —SO ₂ — and B represents —CH ₂ —O— are those of general formula 1j:

Is characterized by
In a preferred embodiment, the invention relates to compounds of formula 1j, in which n, R ¹ , R ² and R ³ may have the meanings indicated above, They may be in the form of enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, and in some cases their solvates. And / or in the form of hydrates.

に従って、又は一般式regio-2：

に従って結合されているが、基Ａ、Ｂ、Ｒ¹、Ｒ²及びＲ³が、上に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。本発明の特に好ましい化合物は、式regio-2の化合物であり、式中、基Ａ、Ｂ、Ｒ¹、Ｒ²及びＲ³が、上に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。 In the compound of formula 1, the hydroxyl functional group may be bonded to the 3-position of the phenyl ring. Preferred according to the invention are the regioisomers of general formula 1, in which the hydroxyl function is of the general formula regio-1:

Or according to the general formula regio-2:

Wherein the groups A, B, R ¹ , R ² and R ³ may have the meanings described above, and the compounds are optionally individual enantiomers, individual enantiomers or racemates May be in the form of a mixture, optionally in the form of an acid addition salt with a pharmacologically acceptable acid, and optionally in the form of their solvates and / or hydrates. May be. Particularly preferred compounds of the invention are those of the formula regio-2, in which the groups A, B, R ¹ , R ² and R ³ may have the meanings described above, Optionally in the form of individual enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, and optionally They may be in the form of their solvates and / or hydrates.

に従って結合され、及び、式中、ｎ、Ｒ¹、Ｒ²及びＲ³が、上に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。 Of particular importance are therefore compounds of the formula 1a, in which the hydroxyl function is of the general formula regio-2a:

And in the formula, n, R ¹ , R ² and R ³ may have the meanings described above, and the compounds are optionally individual enantiomers, individual enantiomers or racemic compounds. It may be in the form of a mixture, optionally in the form of an acid addition salt with a pharmacologically acceptable acid, and optionally in the form of their solvates and / or hydrates. There may be.

に従って結合され、及び、式中、ｎ、Ｒ¹、Ｒ²及びＲ³が、上に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。 Of particular importance are therefore compounds of the formula 1b, in which the hydroxyl function is of the general formula regio-2b:

And in the formula, n, R ¹ , R ² and R ³ may have the meanings described above, and the compounds are optionally individual enantiomers, individual enantiomers or racemic compounds. It may be in the form of a mixture, optionally in the form of an acid addition salt with a pharmacologically acceptable acid, and optionally in the form of their solvates and / or hydrates. There may be.

に従って結合され、及び、式中、ｎ、Ｒ¹、Ｒ²及びＲ³が、上に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。 Of particular importance are therefore compounds of the formula 1c, in which the hydroxyl function is of the general formula regio-2c:

And in the formula, n, R ¹ , R ² and R ³ may have the meanings described above, and the compounds are optionally individual enantiomers, individual enantiomers or racemic compounds. It may be in the form of a mixture, optionally in the form of an acid addition salt with a pharmacologically acceptable acid, and optionally in the form of their solvates and / or hydrates. There may be.

に従って結合され、及び、式中、ｎ、Ｒ¹、Ｒ²及びＲ³が、上に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。 Of particular interest are therefore compounds of the formula 1d, in which the hydroxyl function is of the general formula regio-2d:

And in the formula, n, R ¹ , R ² and R ³ may have the meanings described above, and the compounds are optionally individual enantiomers, individual enantiomers or racemic compounds. It may be in the form of a mixture, optionally in the form of an acid addition salt with a pharmacologically acceptable acid, and optionally in the form of their solvates and / or hydrates. There may be.

に従って結合され、及び、式中、ｎ、Ｒ¹、Ｒ²及びＲ³が、上に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。 Of particular importance are therefore compounds of the formula 1e, in which the hydroxyl function is of the general formula regio-2e:

And in the formula, n, R ¹ , R ² and R ³ may have the meanings described above, and the compounds are optionally individual enantiomers, individual enantiomers or racemic compounds. It may be in the form of a mixture, optionally in the form of an acid addition salt with a pharmacologically acceptable acid, and optionally in the form of their solvates and / or hydrates. There may be.

に従って結合され、及び、式中、ｎ、Ｒ¹、Ｒ²及びＲ³が、上に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。 Of particular interest are therefore compounds of the formula 1g, in which the hydroxyl function is of the general formula regio-2g:

And in the formula, n, R ¹ , R ² and R ³ may have the meanings described above, and the compounds are optionally individual enantiomers, individual enantiomers or racemic compounds. It may be in the form of a mixture, optionally in the form of an acid addition salt with a pharmacologically acceptable acid, and optionally in the form of their solvates and / or hydrates. There may be.

に従って結合され、及び、式中、ｎ、Ｒ¹、Ｒ²及びＲ³が、上に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。 Of particular importance are therefore compounds of the formula 1h, in which the hydroxyl function is of the general formula regio-2h:

And in the formula, n, R ¹ , R ² and R ³ may have the meanings described above, and the compounds are optionally individual enantiomers, individual enantiomers or racemic compounds. It may be in the form of a mixture, optionally in the form of an acid addition salt with a pharmacologically acceptable acid, and optionally in the form of their solvates and / or hydrates. There may be.

に従って結合され、及び、式中、ｎ、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴及びＲ⁵が、上に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。 Of particular importance are therefore compounds of the formula 1i, in which the hydroxyl function is of the general formula regio-2i:

And in the formula, n, R ¹ , R ² , R ³ , R ⁴ and R ⁵ may have the meanings described above, and the compounds optionally have individual enantiomers, individual In the form of a mixture of enantiomers or racemates, optionally in the form of an acid addition salt with a pharmacologically acceptable acid, and optionally in the form of their solvates and / or It may be in the form of a hydrate.

に従って結合され、及び、式中、ｎ、Ｒ¹、Ｒ²及びＲ³が、上に記載した意味を有していてもよく、化合物は、場合により個々のエナンチオマー、個々のエナンチオマー又はラセミ化合物の混合物の形態にあってもよく、場合により薬理学的に許容可能な酸との酸付加塩の形態にあってもよく、及び、場合によりそれらの溶媒和物及び／又は水和物の形態にあってもよい。 Of particular importance are therefore compounds of the formula 1j, in which the hydroxyl function is of the general formula regio-2j:

And in the formula, n, R ¹ , R ² and R ³ may have the meanings described above, and the compounds are optionally individual enantiomers, individual enantiomers or racemic compounds. It may be in the form of a mixture, optionally in the form of an acid addition salt with a pharmacologically acceptable acid, and optionally in the form of their solvates and / or hydrates. There may be.

In the compound of formula 1, the groups R ¹ and R ² are arranged in the ortho or meta position relative to the bond of the benzyl to the “—CH ₂ ” group in each case if they do not represent hydrogen. May be. If none of the radicals R ¹ and R ² do not represent hydrogen, in accordance with the present invention, both radicals R ¹ and both R ² is in ortho arrangement or the radicals R ¹ and R ² in the meta arrangement Formula 1 It is particularly important to use compounds of the formula 1 in which both groups R ¹ and R ² are in the meta configuration. In compounds of formula 1 in which one of the radicals R ¹ and R ² does not represent hydrogen, this radical may be in the ortho or meta configuration relative to the bond of benzene to “—CH ₂ ”. In this case, it is particularly preferred according to the invention to use compounds of the formula 1 in which the radical R ¹ or R ² which does not represent hydrogen is in the ortho configuration.

Also, particularly preferred may optionally be in the form of individual enantiomers, individual enantiomers or racemic compounds, and optionally in the form of acid addition salts with pharmacologically acceptable acids. A compound of the general formula 1 selected from the following, which may optionally be in the form of solvates and / or hydrates thereof:
8-hydroxy-5- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -1H-quinolin-2-one;
5- {2- [2- (2,4-Difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -8-hydroxy-3,4-dihydro-1H-quinoline-2 -on;
8-hydroxy-5- {1-hydroxy-2- [2- (4-hydroxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -1H-quinolin-2-one;
5- {2- [2- (4-Fluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -8-hydroxy-3,4-dihydro-1H-quinolin-2-one ;
7-hydroxy-5- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -1H-quinolin-2-one;
5- {2- [2- (3,5-difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -7-hydroxy-1H-quinolin-2-one;
7-Hydroxy-5- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -3,4-dihydro-1H-quinolin-2-one ;
5- {2- [2- (4-Ethoxy-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -7-hydroxy-3,4-dihydro-1H-quinolin-2-one ;
4-hydroxy-7- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -3H-benzoxazol-2-one;
4-hydroxy-7- {1-hydroxy-2- [2- (4-hydroxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -3H-benzoxazol-2-one;
5-hydroxy-8- {1-hydroxy-2- [2- (4-hydroxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -2,2-dimethyl-4H-benzo [1,4 ] Oxazin-3-one;
5-hydroxy-7- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -3H-benzoxazol-2-one;
7- {2- [2- (4-Ethoxy-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -5-hydroxy 3H-benzoxazol-2-one;
6-Hydroxy-8- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -2,2-dimethyl-4H-benzo [1,4 ] Oxazin-3-one;
8- {2- [2- (4-Fluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy 2,2-dimethyl-4H-benzo [1,4] Oxazin-3-one and
5-hydroxy-8- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -2,2-dimethyl-4H-benzo [1,4 ] Oxazin-3-one.

In another aspect, the invention relates to the above novel compounds of formula 1 as pharmaceutical compositions. The invention also relates to the use of the above compounds of general formula 1 for the manufacture of a pharmaceutical composition for the treatment of respiratory diseases. The present invention preferably comprises obstructive pulmonary disease of various origins, emphysema of various origins, restrictive lung disease, interstitial pulmonary disease, cystic fibrosis, bronchitis of various origins, It relates to the use of the above compounds of general formula 1 for the manufacture of a pharmaceutical composition for the treatment of respiratory diseases selected from bronchiectasis, ARDS (adult respiratory distress syndrome) and many forms of pulmonary edema.
Compound of general formula 1 for producing a pharmaceutical composition for the treatment of obstructive pulmonary disease selected from COPD (chronic obstructive pulmonary disease), bronchial asthma, childhood asthma, severe asthma attack, acute asthma attack and chronic bronchitis Is preferred.
Also preferred is the use of compounds of general formula 1 for the manufacture of pharmaceutical compositions for the treatment of emphysema that have their origin in α1-proteinase inhibitor deficiency or COPD (chronic obstructive pulmonary disease).
Also, allergic alveolitis, restrictive lung diseases caused by work-related toxic substances, such as asbestos (lung) or silicosis (symptoms), and restrictions caused by lung tumors, such as cancerous lymphangiopathy, Preference is given to the use of compounds of the general formula 1 for preparing a pharmaceutical composition for the treatment of restrictive lung disease selected from bronchioloalveolar carcinoma and lymphoma.

Also, pneumonia caused by infections such as viruses, bacteria, fungi, protozoa, helminths or other pathogens, pneumonia caused by various factors such as aspiration and left heart failure, radiation Inducible pneumonia or fibrosis, collagen disease such as lupus lupus erythematosus, systemic scleroderma or sarcoidosis, granulomatosis such as Boeck's disease, idiopathic interstitial pneumonia or idiopathic lung It is preferred to use a compound of general formula 1 for preparing a pharmaceutical composition for the treatment of interstitial lung disease selected from fibrosis (IPF).
Also preferred is the use of a compound of general formula 1 for preparing a pharmaceutical composition for the treatment of cystic fibrosis or cystic fibrosis.
Also preferred is the use of compounds of general formula 1 for the preparation of a pharmaceutical composition for the treatment of bronchitis, for example bronchitis caused by bacterial or viral infections, allergic bronchitis and toxic bronchitis.
Also preferred is the use of a compound of general formula 1 for preparing a pharmaceutical composition for the treatment of bronchiectasis.
Also preferred is the use of a compound of general formula 1 for preparing a pharmaceutical composition for the treatment of ARDS (adult respiratory distress syndrome).
Also preferred is the use of compounds of general formula 1 for the preparation of a pharmaceutical composition for the treatment of pulmonary edema, for example toxic pulmonary edema after inhalation or inhalation of toxic and foreign substances.

（式中、基ｎ、Ａ、Ｂ、Ｒ¹、Ｒ²及びＲ³は、上に記載した意味を有していてもよい）により表すことができる。 Particularly preferably, the present invention relates to the use of a compound of formula 1 for the manufacture of a pharmaceutical composition for the treatment of asthma or COPD. Also of particular importance is to produce a pharmaceutical composition for once-daily treatment of inflammatory and obstructive respiratory diseases, in particular for once-daily treatment of asthma or COPD. The above use of a compound of formula 1
Furthermore, the present invention relates to a method for treating the above diseases, characterized in that one or more of the above compounds of general formula 1 are administered in a therapeutically effective amount. The present invention preferably relates to a method of treating asthma or COPD, characterized in that one or more of the above compounds of general formula 1 are administered once a day in a therapeutically effective amount.
In another aspect, the invention relates to the above novel compounds of formula 1 in the form of individual optical isomers, individual enantiomers or racemic mixtures. Particularly preferred are compounds of formula 1 in the form of enantiomerically pure compounds, but the R-enantiomer of compounds of formula 1 has particular importance according to the invention. The R-enantiomer of the compound of formula 1 has the general formula R-1:

Wherein the groups n, A, B, R ¹ , R ² and R ³ may have the meanings described above.

Methods for separating racemates into individual enantiomers are known in the art and can be used to produce enantiomerically pure R- or S-enantiomers of compounds of formula 1 as well. it can.
In another aspect, the present invention is in the form of an acid addition salt with a pharmacologically acceptable acid, and optionally in the form of a solvate and / or hydrate thereof. Relates to the above compound of formula 1.
Acid addition salts with pharmacologically acceptable acids, for example, hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydro Acetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate A salt selected from fete, hydrophosphate, hydrofumarate and hydromethanesulfonate is meant.
Of the acid addition salts, salts of hydrochloric acid, maleic acid, fumaric acid and acetic acid are particularly preferred according to the present invention.

Unless otherwise stated, an alkyl group is a straight or branched alkyl group having 1 to 4 carbon atoms. The following are mentioned by way of example: methyl, ethyl, propyl or butyl. In some cases, the abbreviations Me, Et, Prop or Bu are used to indicate the groups methyl, ethyl, propyl or butyl. Unless stated otherwise, the definitions propyl and butyl include all possible isomeric systems of the group. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl, tert-butyl, and the like.
Unless otherwise stated, alkylene groups are branched and unbranched double bond alkyl bridges having 1 to 4 carbon atoms. Examples include methylene, ethylene, n-propylene or n-butylene.
Unless otherwise stated, alkyloxy groups (O-alkyl or alkoxy groups) are branched and unbranched alkyl groups having 1 to 4 carbon atoms attached through an oxygen atom. Examples are: methyloxy, ethyloxy, propyloxy or butyloxy. In some cases, the abbreviations MeO-, EtO-, PropO- or BuO- can be used to indicate a methyloxy, ethyloxy, propyloxy or butyloxy group. Unless stated otherwise, the definitions propyloxy and butyloxy include all possible isomeric systems of the group. Thus, for example, propyloxy includes n-propyloxy and iso-propyloxy, butyloxy includes iso-butyloxy, sec-butyloxy, tert-butyloxy, and the like. In some cases, the term alkoxy can be used in place of alkyloxy within the scope of the present invention. The groups methyloxy, ethyloxy, propyloxy or butyloxy can thus refer to methoxy, ethoxy, propoxy or butoxy by their names.
Halogen within the scope of the present invention represents fluorine, chlorine, bromine or iodine. Unless stated to the contrary, fluorine, chlorine and bromine are the preferred halogens.
The compounds of the present invention can be prepared analogously to methods already known in the art. Suitable manufacturing methods are described, for example, in US Pat. No. 4,460,581, which is included in this respect as a reference.
The following examples serve to illustrate the invention in greater detail without limiting the invention to the subject matter described by way of example.

Intermediate synthesis
Intermediate process: 5-Benzyloxy-7- (2-ethoxy-2-hydroxy-acetyl) 3H-benzoxazol-2-one

a) 1- (5-Benzyloxy-2-hydroxy-3-nitro-phenyl) -ethanone 700 mL of acetic acid while cooling 18 mL of fuming nitric acid using an ice bath so that the temperature does not exceed 20 ° C. In a solution of 81.5 g of (0.34 mol) 1- (5-benzyloxy-2-hydroxy-phenyl) -ethanone (known from US 4,460,581). The reaction mixture was then stirred at ambient temperature for 2 hours, poured into ice water and filtered. The product was recrystallized from isopropanol, suction filtered and washed with isopropanol and diisopropyl ether. Yield: 69.6 g (72%); mass spectrometry [M + H] ⁺ = 288.
b) 1- (3-Amino-5-benzyloxy-2-hydroxy-phenyl) -ethanone 69.5 g (242 mmol) 1- (5-benzyloxy-2-hydroxy-3-nitro-phenyl) -ethanone Dissolved in 1.4 L of methanol and hydrogenated in the presence of 14 g of rhodium on charcoal (10%) as catalyst at 3 bar and at ambient temperature. The catalyst was then filtered and the filtrate was evaporated. The remainder was further reacted without further purification.
Yield: 60.0 g (96%), _Rf value = 0.45 (dichloromethane on silica gel).

c) 7-acetyl-5-benzyloxy-3H-benzoxazol-2-one 52 g (0.53 mol) of phosgene at 20-40 ° C. in 121 g (0.47 mol) 1- ( It was piped into a solution of 3-amino-5-benzyloxy-2-hydroxy-phenyl) -ethanone. The reaction mixture was heated to 50 ° C. for 2 hours, then poured onto ice and acidified with concentrated hydrochloric acid. The reddish brown solid was separated and recrystallized repeatedly from ethanol with the addition of activated charcoal.
Yield 67.5 g (50.6%); Melting range: 163-166 ° C.
d) 20 g (71 mmol) of 5-benzyloxy-7- (2-ethoxy-2-hydroxy-acetyl) -3H-benzoxazol-2-one 7-acetyl-5-benzyloxy-3H-benzoxazole-2- On and 8 g (72 mmol) of selenium dioxide were stirred at reflux temperature for 8 hours in the presence of activated carbon in 100 mL dioxane and 3.1 mL water. The solid was filtered, the solvent was distilled and the remainder was combined with 50 mL ethanol. The mixture was refluxed for 15 minutes and then filtered through activated carbon. The solid which precipitates on cooling is suction filtered for 3 hours and washed with ethanol and diethyl ether.
Yield 7 g (29%); melting range: 140-143 ° C.

Intermediate step 2: 6-Benzyloxy-8- (2-ethoxy-2-hydroxy-acetyl) -2,2-dimethyl-4H-benzo [1,4] oxazin-3-one

a) N- (3-acetyl-5-benzyloxy-2-hydroxy-phenyl) -2-bromo-2-methyl-propionamide 4.64 g (25 mmol) of 2-bromo-2-methyl-propionic acid chloride To a solution of 5.15 g (20 mmol) of 1- (3-amino-5-benzyloxy-2-hydroxy-phenyl) -ethanone in 20 mL of pyridine at 5-20 ° C. After the addition was complete, the mixture was stirred for 15 minutes, combined with ice water and 100 mL ethyl acetate and acidified with concentrated hydrochloric acid. The organic phase was separated, washed with water and dried over sodium sulfate. After the solvent was distilled, the remainder was recrystallized from a diethyl ether / petroleum ether mixture. Yield: 6.8 g (84%); Melting range: 88-90 ° C.
b) 8-acetyl-6-benzyloxy-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one 6.60 g (16.2 mmol) of N- (3-acetyl-5-benzyloxy 2-Hydroxy-phenyl) -2-bromo-2-methyl-propionamide and 2.76 g (20 mmol) potassium carbonate were stirred at 70 mL of acetonitrile at reflux for 1 hour. The solid was filtered off with suction, the filtrate was evaporated and the remainder was combined with 30 mL of ethyl acetate. After further filtration and after distillation of the solvent, the crude product was recrystallized from a small amount of methanol.
Yield: 1.00 g (19%); mass spectrometry [M + H] ⁺ = 326; melting range: 148-150 ° C.

c) 6-Benzyloxy-8- (2-ethoxy-2-hydroxy-acetyl) -2,2-dimethyl-4H-benzo [1,4] oxazin-3-one compound for intermediate step 1d) Prepared from 8-acetyl-6-benzyloxy-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one as described.
Intermediate step 3: 4-Benzyloxy-7- (2-ethoxy-1,2-dihydroxy-ethyl) -3H-benzoxazol-2-one

a) 7-Acetyl-4-benzyloxy-3H-benzoxazol-2-one 41 mL of phenyl chloroformate is added as soon as the temperature rises to 75 ° C., 47 g (183 mmol) of 1- (3 -Amino-4-benzyloxy-2-hydroxy-phenyl) -ethanone (known from US 4,460,581) was added dropwise. The mixture was stirred for 4 hours at 90-95 ° C., poured onto ice and acidified with hydrochloric acid. The precipitated solid was filtered off with suction, washed with diethyl ether and heated at reflux in 500 mL of 95% acetonitrile for 30 minutes. After cooling, the solid was filtered and washed with acetonitrile and diethyl ether.
Yield: 50 g (97%); melting range: 242-244 ° C.
b) 4-Benzyloxy-7- (2-ethoxy-1,2-dihydroxy-ethyl) -3H-benzoxazol-2-one 49.5 g (175 mmol) of 7-acetyl-4-benzyloxy-3H-benzo Oxazol-2-one and 19.6 g (177 mmol) of selenium dioxide were refluxed in 200 mL dioxane and 8 mL water in the presence of activated carbon for 8 hours. The insoluble constituents were filtered off with suction, the solvent was distilled off and the remainder was combined with 150 mL of ethanol. The mixture was refluxed for 30 minutes and then filtered through activated carbon. After the addition of crystallization aid, the product precipitated from the cooled solution. It was suction filtered and washed with ethanol and diethyl ether.

Yield: 30 g (50%); melting range: 153-155 ° C.
Intermediate step 4: 5-Benzyloxy-8- (2-ethoxy-2-hydroxy-acetyl) -2,2-dimethyl-4H-benzo [1,4] oxazin-3-one

a) 215 mL of 8-acetyl-5-benzyloxy-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one 28 g (0.15 mol) 2-bromo-2-methyl-propionic acid chloride Was added dropwise to 25.7 g (0.10 mol) 1- (3-amino-4-benzyloxy-2-hydroxy-phenyl) -ethanone and 41 g (0.30 mol) potassium carbonate in acetonitrile. After stirring for 8 hours at reflux temperature, the solid was filtered off, the filtrate was evaporated and the residue was crystallized from ethanol. Yield: 11.2 g (35%); melting range = 124-126 ° C.
b) 5-Benzyloxy-8- (2-ethoxy-2-hydroxy-acetyl) -2,2-dimethyl-4H-benzo [1,4] oxazin-3-one

9.6 g (30 mmol) of 8-acetyl-5-benzyloxy-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one, 3.3 g (30 mmol) of selenium dioxide and activated carbon Stir at reflux temperature for 90 hours in dioxane and 2 mL water. The solid was filtered off with suction, the filtrate was evaporated and the remainder was refluxed in 100 ml of ethanol for 30 minutes. The solvent was distilled and the remainder was dissolved in 125 mL ethyl acetate. It was subsequently extracted with potassium carbonate and water, dried with sodium sulphate and evaporated. The remaining oil (10.1 g) was further reacted directly.
Intermediate process 5: 8-Benzyloxy-5-oxiranyl-1H-quinolin-2-one

a) 8-Benzyloxy-5 (2-chloro-acetyl) -1H-quinolin-2-one 25.2 g (86 mmol) of 5-acetyl-8-benzyloxy-1H- in 500 mL of dichloroethane and 300 ml of methanol Quinolin-2-one (European Journal of Medicianl Chemistry 1984, 19 (4), 341) and 50 g (142 mmol) of benzyltrimethylammonium dichloriodate were stirred at reflux temperature overnight. The reaction mixture was evaporated and the remainder was stirred in THF and 1N hydrochloric acid overnight. After the THF was distilled, the precipitated solid was filtered off with suction, washed with diethyl ether and dried.
Yield: 23.6 g (84%); mass spectrometry [M + H] ⁺ = 328/30.

b) 8-Benzyloxy-5- (2-chloro-1-hydroxy-ethyl) -1H-quinolin-2-one A solution of 238 mL of 2 molar lithium borohydride in THF was charged with 52 g (159 mmol) of 8 in 650 mL. -Benzyloxy-5- (2-chloro-acetyl) -1H-quinolin-2-one was added dropwise at 0 ° C. It was stirred for 2 hours at 0 ° C., then heated to ambient temperature, combined with 200 mL dichloromethane and 75 mL water and stirred for an additional hour. The precipitated solid was filtered off with suction and the organic phase of the filtrate was separated and removed from the solvent. The remainder was combined with the solid from the previous filtrate and stirred repeatedly with diethyl ether and THF. Yield: 51.6 g (99%); mass spectrometry [M + H] ⁺ = 330/32.
c) 8-Benzyloxy-5- oxiranyl -1H-quinolin-2-one 20 g (61 mmol) of 8-benzyloxy-5- (2-chloro-1-hydroxy-ethyl) -1H-quinoline in 160 mL of DMF The solution of 2-one was added dropwise at 0 ° C. to 35 mL of 4 molar sodium hydroxide solution and then stirred at this temperature for 2 hours. The reaction mixture was combined with 1.5 L ice water, buffered by the addition of dry ice, and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, the solvent was distilled off and the residue was chromatographed on aluminum oxide (dichloromethane / ethyl acetate gradient). The fraction-containing product was evaporated to 60 mL and then combined with petroleum ether, which was suction filtered and dried while the solid precipitated. Yield: 9 g (48%); mass spectrometry [M + H] ⁺ = 294.
Intermediate step 6: 7-Benzyloxy-5-oxiranyl-1H-quinolin-2-one

a) Phenyl 2-acetyl-4-benzyloxy-6-nitro-trifluoromethanesulfonate 92.7 mL (660 mmol) triethylamine in 90 g (313 mmol) 1- (5-benzyloxy-2- phenyl ) in 940 mL dichloromethane To the hydroxy-3-nitro-phenyl) -ethanone was added at -10 ° C. 65 mL (394 mmol) of trifluoromethanesulfonic anhydride and 40 mL of dichloromethane were then slowly added dropwise. After 15 minutes of stirring at −5 ° C., the reaction was stopped by careful addition of 400 mL ammonium chloride solution and 400 mL sodium bicarbonate solution. The organic phase was separated, dried with sodium sulfate and evaporated. The remainder was dissolved in 150 mL diethyl ether and then precipitated by the addition of 800 mL hexane. The solid was filtered, suspended in a diethyl ether / hexane mixture and suction filtered again.
Yield: 118 g (90%); mass spectrometry; [M + H] ⁺ = 420.

b) Methyl 3- (2-acetyl-4-benzyloxy-6-nitro-phenyl) -acrylate 5.88 g (6.42 mmol) of tris- (dibenzylideneacetone) -dipalladium, 3.50 g (12. 01 mmol) butylphosphonium tri-tert-tetrafluoroborate, 81.2 mL (371 mmol) dicyclohexylmethylamine, 105.8 g (286 mmol) tetrabutylammonium iodide and 32.6 mL (362 mmol) methyl acrylate, To a solution of 100 g (238 mmol) phenyl 2-acetyl-4-benzyloxy-6-nitro-trifluoromethanesulfonate in 360 mL dioxane. The reaction mixture was stirred for 2 hours at 80 ° C. under a nitrogen atmosphere and then combined with 2 L of diethyl ether and 500 g of silica gel. After 10 minutes, the silica gel was suction filtered, but again washed repeatedly with diethyl ether. The combined organic phases were subsequently washed with 1N hydrochloric acid, sodium carbonate solution and sodium chloride solution. The solvent was distilled and the residue recrystallized from ethanol and solid was filtered and washed with ethanol. Yield: 32.2 g (38%); mass spectrometry: [M + H] ⁺ = 356.

c) 5-acetyl-7-benzyloxy-3,4-dihydro-1H-quinolin-2-one 5.0 g (14.07 mmol) of methyl 3- (2-acetyl-4-benzyloxy-6-nitro-) Phenyl) -acrylate was hydrogenated at 4 bar using 100 mL ethanol combined with Raney nickel as catalyst. The catalyst was separated and the filtrate was acidified with 15 mL of 2N hydrochloric acid. The product that crystallizes was filtered off with suction and dried. Yield: 1.0 g (24%); mass spectrometry: [M + H] ⁺ = 296.
d) 5-acetyl-7-benzyloxy-1H-quinolin-2-one 13.0 g (44 mmol) of 5-acetyl-7-benzyloxy-3,4-dihydro-1H-quinolin-2-one in 130 mL In dioxane and combined with 15.0 g (66 mmol) of 2,3-dichloro-5,6-dicyanobenzoquinone. The mixture was refluxed for 30 minutes, cooled to ambient temperature and stirred for a further 2 hours. The solid was filtered, washed with dioxane and dissolved in 600 mL dichloromethane / methanol (9: 1). The solution was washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated. The remainder was then suspended in methanol, filtered and dried. Production: 8.3 g (64%); mass spectrometry: [M + H] ⁺ = 294.

e) 7-benzyloxy-5- (2-chloro-acetyl) -1H-quinolin-2-one 7.0 g (23.9 mmol) of 5-acetyl-7-benzyloxy-1H-quinolin-2-one and 19.0 g (54.6 mmol) of benzyltrimethylammonium dichloriodate was stirred at 65 ° C. in 43 mL acetic acid, 7 mL water and 147 mL dichloroethane. After 4.5 hours, the reaction was stopped by the addition of 400 mL sodium carbonate solution and 50 mL 5% sodium bisulfite solution. Insoluble constituents were filtered off with suction, washed with water and dried.
Production: 6.0 g (77%); mass spectrometry: [M + H] ⁺ = 328.
f) 7-benzyloxy-5- oxiranyl -1H-quinolin-2-one 6.0 g (18.3 mmol) of 7-benzyloxy-5- (2-chloro-acetyl) -1H-quinolin-2-one Placed in 150 mL of tetrahydrofuran and combined with 434 mg (819.9 mmol) of lithium borohydride at 0-5 ° C. The mixture was stirred for 30 minutes, then 43 mL of 2.5 molar sodium hydroxide solution was added and the mixture was stirred for an additional 4 hours with heating to ambient temperature. The mixture was combined with sodium chloride solution, filtered and extracted repeatedly with ethyl acetate / tetrahydrofuran (1: 1). The filtered solid and organic phases were removed from the combination and solvent. The rest was suspended in methanol, suction filtered and dried.
Yield 4.8 g (89%); mass spectrometry: [M + H] ⁺ = 294.

Synthesis of final compounds
Example 1: 8-Hydroxy-5- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -1H-quinolin-2-one

a) 587 mg (2 mmol ) of 8-benzyloxy-5- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -1H-quinolin-2-one ) Of 8-benzyloxy-5-oxiranyl-1H-quinolin-2-one and 358 mg (2 mmol) of 2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamine in 5 mL of n-butanol. Stir for 140 hours. The solvent was then distilled and the remainder was purified by chromatography (reverse phase; water / acetonitrile gradient).
Yield: 306 mg (32%); mass spectrometry; [M + H] ⁺ = 473.
b) 8-hydroxy-5- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -1H-quinolin-2-one 306 mg (0. 6 mmol) of 8-benzyloxy-5- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -1H-quinolin-2-one, Dissolved in 10 mL methanol and hydrogenated at ambient temperature and pressure using palladium on charcoal as catalyst. The catalyst was then separated and the filtrate was removed from the solvent.
Yield: 145 mg (59%); mass spectrometry [M + H] ⁺ = 389.

Example 2: 5- {2- [2- (2,4-Difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -8-hydroxy-3,4-dihydro-1H -Quinolin-2-one

a) 8-Benzyloxy-5- {2- [2- (2,4-difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -1H-quinolin-2-one 587 mg (2 mmol) 8-benzyloxy-5-oxiranyl-1H-quinolin-2-one and 555 mg (3 mmol) 2- (2,4-difluoro-phenyl) -1,1-dimethyl-ethylamine are reacted and Prepared as described for Example 1a). Yield: 220 mg (23%); mass spectrometry [M + H] ⁺ = 479.
b) 5- {2- [2- (2,4-Difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -8-hydroxy-3,4-dihydro-1H-quinoline 2-one 220 mg (0.5 mmol) 8-benzyloxy-5- {2- [2- (2,4-difluoro-phenyl) -1,1-dimethyl-ethylamino] -1- in 10 mL methanol A solution of hydroxy-ethyl} -1H-quinolin-2-one was hydrogenated at ambient temperature and pressure in the presence of palladium on charcoal. The catalyst was then separated, the filtrate evaporated and the remainder chromatographed (reverse phase; water / acetonitrile gradient).
Yield: 56 mg (31%); mass spectrometry [M + H] ⁺ = 391.

The following compounds (Examples 3-5, 7 and 8) can also be obtained analogously to the synthetic examples given above:
Example 3: 8-Hydroxy-5- {1-hydroxy-2- [2- (4-hydroxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -1H-quinolin-2-one

Example 4: 5- {2- [2- (4-Fluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -8-hydroxy-3,4-dihydro-1H-quinoline -2-one

Example 5: 7-Hydroxy-5- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -1H-quinolin-2-one

a) 7-Benzyloxy-5- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -1H-quinolin-2-one 150 mg (0 .51 mmol) 7-benzyloxy-5-oxiranyl-1H-quinolin-2-one and 208 mg (1.2 mmol) 2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamine in 1 mL isopropanol And irradiated with microwaves at 135 ° C. for a total of 1 hour. The reaction mixture was then combined with ethyl acetate and 0.5 molar tartaric acid as soon as a precipitate was formed. The organic phase was discarded and the solid and aqueous phases were extracted with dichloromethane / methanol. The combined organic phases were evaporated and combined with 8 mL ethyl acetate. The insoluble solid was filtered off with suction and dried. Yield: 130 mg (54%).
b) 7-hydroxy-5- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -1H-quinolin-2-one 128 mg (0. 27 mmol) of 7-benzyloxy-5- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -1H-quinolin-2-one, Dissolved in 12 mL methanol and hydrogenated using palladium on charcoal as catalyst. The reaction mixture was filtered through celite, eluted with methanol and the filtrate was removed from the solvent. Yield: 65 mg (63%); R _f = 0.25 (silica gel, dichloromethane / methanol / ammonia = 18: 2: 1).

Example 6: 5- {2- [2- (3,5-Difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -7-hydroxy-1H-quinolin-2-one

Example 7: 7-Hydroxy-5- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -3,4-dihydro-1H-quinoline -2-one

Example 8: 5- {2- [2- (4-Ethoxy-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -7-hydroxy-3,4-dihydro-1H-quinoline -2-one

Example 9: 4-Hydroxy-7- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -3H-benzoxazol-2-one

172 mg (0.5 mmol) 4-benzyloxy-7- (2-ethoxy-1,2-dihydroxy-ethyl) -3H-benzoxazol-2-one and 90 mg (0.5 mmol) 2 in 8 mL ethanol. -(4-Methoxy-phenyl) -1,1-dimethyl-ethylamine was stirred for 90 minutes at 80 ° C. After cooling to ambient temperature, 19 mg (0.5 mmol) sodium borohydride was added. The mixture was stirred for a further 2 hours, acidified with 1N hydrochloric acid, stirred for 10 minutes and the alkali was made with potassium carbonate solution. The mixture was combined with 40 mL ethyl acetate and filtered through diatomaceous earth. The filtrate was evaporated and the remainder was purified by chromatography (reverse phase with 0.1% trifluoroacetic acid, acetonitrile / water gradient). The resulting benzyl ether was therefore dissolved in 5 mL of ethanol and hydrogenated at 2.5 bar hydrogen gas pressure in the presence of palladium on charcoal (10%). The catalyst was then separated and the filtrate was removed from the solvent.
Yield: 20 mg (8%, trifluoroacetic acid), mass spectrometry [M + H] ⁺ = 373.

Example 10: 4-hydroxy-7- {1-hydroxy-2- [2- (4-hydroxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -3H-benzoxazol-2-one

The compound was prepared as in Example 9 with 172 mg (0.5 mmol) 4-benzyloxy-7- (2-ethoxy-1,2-dihydroxy-ethyl) -3H-benzoxazol-2-one and 83 mg (0 .5 mmol) of 4- (2-amino-2-methyl-propyl) -phenol.
Yield: 29 mg (12%, trifluoroacetic acid); mass spectrometry [M + H] ⁺ = 359.

Example 11 :: 5-hydroxy-8- {1-hydroxy-2- [2- (4-hydroxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -2,2-dimethyl-4H- Benzo [1,4] oxazin-3-one

Example 12: 5-hydroxy-7- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -3H-benzoxazol-2-one

172 mg (0.5 mmol) 5-benzyloxy-7- (2-ethoxy-2-hydroxy-acetyl) -3H-benzoxazol-2-one and 90 mg (0.5 mmol) 2- (4-methoxy-phenyl) ) -1,1-dimethyl-ethylamine was obtained in the same manner as described for Example 9.
Yield: 88 mg (36%, trifluoroacetic acid); mass spectrometry [M + H] ⁺ = 373.

Example 13: 7- {2- [2- (4-Ethoxy-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -5-hydroxy-3H-benzoxazol-2-one

172 mg (0.5 mmol) 5-benzyloxy-7- (2-ethoxy-2-hydroxy-acetyl) -3H-benzoxazol-2-one and 97 mg (0.5 mmol) 2- (4-ethoxy-phenyl) ) -1,1-dimethyl-ethylamine was prepared in the same manner as described for Example 9.
Yield: 41 mg (16%, trifluoroacetic acid); mass spectrometry [M + H] ⁺ = 387.

Example 14: 6-hydroxy-8- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -2,2-dimethyl-4H-benzo [1,4] oxazin-3-one

385 mg (1 mmol) of 6-benzyloxy-8- (2-ethoxy-2-hydroxy) -2,2-dimethyl-4H-benzo [1,4] oxazin-3-one and 179 mg (1 mmol) 2- (4 -Methoxy-phenyl) -1,1-dimethyl-ethylamine was stirred in 5 mL of tetrahydrofuran for 30 minutes at 50 ° C. The mixture was cooled to 0 ° C. and combined with 1.5 mL of 2 molar lithium borohydride solution in tetrahydrofuran. The mixture was stirred for 30 minutes at 0 ° C. and then 10 mL of dichloromethane and 3 mL of water were added. The mixture was stirred for 1 hour at ambient temperature and filtered through porous diatomaceous earth, eluting with dichloromethane. The filtrate was evaporated and the residue was purified by chromatography (reverse phase with 0.1% trifluoroacetic acid, acetonitrile / water gradient). The resulting benzyl ether was therefore dissolved in methanol and hydrogenated at 2.5 bar hydrogen gas pressure and ambient temperature using palladium on charcoal (10%) as catalyst. The catalyst was separated, the solvent was distilled and the remainder was purified by chromatography.
Yield: 144 mg (27%, trifluoroacetic acid); mass spectrometry [M + H] ⁺ = 415.

Example 15: 8- {2- [2- (4-Fluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one

a) 6-Benzyloxy-8- {2- [2- (4-fluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -2,2-dimethyl-4H-benzo [ 1,4] Oxazin -3-one 385 mg (1 mmol) of 6-benzyloxy-8- (2-ethoxy-2-hydroxy-acetyl) -2,2-dimethyl-4H-benzo [1,4] oxazine-3 -On and 167 mg (1 mmol) of 2- (4-fluoro-phenyl) -1,1-dimethyl-ethylamine were reacted and made up as in Example 14. However, the resulting benzyl ether was chromatographed on a silica gel column (dichloromethane / methanol gradient).
Yield: 290 mg (59%); mass spectrometry [M + H] ⁺ = 493.

b) 8- {2- [2- (4-Fluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-2,2-dimethyl-4H-benzo [1 , 4] Oxazin-3-one 280 mg (0.57 mmol) of 6-benzyloxy-8- {2- [2- (4-fluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy- Ethyl} -2,2-dimethyl-4H-benzo [1,4] oxazin-3-one was dissolved in 7 mL of methanol and hydrogenated with palladium on charcoal (10%) at ambient temperature. The catalyst was then separated and the filtrate was removed from the solvent. The remainder was dissolved in dichloromethane and precipitated by addition of methanol / water. White solid.
Yield: 90 mg (39%); mass spectrometry [M + H] ⁺ = 401.

Example 16: 5-hydroxy-8- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -2,2-diethyl-4H-benzo [1,4] oxazone-3-one

a) 5-Benzyloxy-8- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -2,2-dimethyl-4H-benzo [ 1,4] Oxazin -3-one 10.1 g (26 mmol) of 5-benzyloxy-8- (2-ethoxy-2-hydroxy-acetyl) -2,2-dimethyl-4H-benzo [1,4] oxazine -3-one and 4 g (22 mmol) of 2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamine were stirred in 100 ml of ethanol for 2 hours at 60-70 ° C. After distilling off some of the solvent, the solid precipitated during cooling and was filtered with suction and washed with ethanol and diethyl ether.
Yield: 8.7 g (78%) melting range = 138-140 ° C.

b) 5-Benzyloxy-8- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -2,2-dimethyl-4H-benzo [ 1,4] oxason-3-one 0.6 g of sodium borohydride was added to 8.6 g (17 mmol) of 5-benzyloxy-8- {1-hydroxy-2- [2 ] in 80 mL of ethanol at ambient temperature. -(4-Methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -2,2-dimethyl-4H-benzo [1,4] oxazin-3-one is added and the mixture is Stir for 1 hour. The reaction mixture was combined with 20 mL acetone, stirred for 30 minutes, diluted with 50 mL water and acidified with glacial acetic acid. After the organic solvent was distilled, ethyl acetate was added to the aqueous residue. It was acidified with concentrated hydrochloric acid and diluted with diethyl ether. The product precipitated as the hydrochloride was filtered off with suction and washed with acetone and diethyl ether. Yield: 8.4 g (91%, hydrochloride); melting range = 215-218 ° C.).

c) 5-Benzyloxy-8- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -2,2-dimethyl-4H-benzo [ 1,4] Oxazin-3-one 7.3 g (14 mmol) of 5-benzyloxy-8- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -Ethyl} -2,2-dimethyl-4H-benzo [1,4] oxazin-3-one hydrochloride was hydrogenated in 125 mL of methanol using palladium on charcoal as a catalyst. The catalyst was separated and the solvent was substantially distilled. Acetone was added and the precipitated solid was filtered and washed with acetone and diethyl ether.
Yield: 5.4 g (89%, hydrochloride); melting range = 200 ° C. (decomposition).
Suitable formulations for administering the compound of formula 1 include tablets, capsules, suppositories, solutions, powders and the like. The proportion of pharmaceutically active compound should be in the range of 0.05 to 90% by weight, preferably 0.1 to 50% by weight of the total composition. Suitable tablets are, for example, active substances with known excipients, such as inert diluents such as calcium carbonate, calcium phosphate or lactose, tablet differentiation substances such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as stearic acid. It can be obtained by mixing magnesium or talc and / or agents for delayed release such as carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablet can also include several layers.

Coated tablets are therefore produced by coating the core produced in the same way as tablets with substances normally used for tablet coating, such as Kollidon or shellac, gum arabic, talc, titanium dioxide or sugar. Can do. In order to achieve delayed dissipation or prevent incompatibility, the nucleus can also consist of many layers. Similarly, tablet coatings can consist of many layers to achieve delayed release using the above-described excipients for tablets as much as possible.
A syrup or elixir comprising an active substance or a combination of active substances according to the present invention may further comprise sweeteners such as saccharin, cyclamate, glycerol or sugar and flavor enhancers such as flavoring such as vanillin or orange extract. . They may also contain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
Solutions are prepared in the usual manner, eg with isotonic agents, preservatives such as p-hydroxybenzoates, or stabilizers such as alkali metal salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and / or dispersants. However, when water is used as a diluent, for example, an organic solvent may also be used, optionally as a solvent agent or dissolution aid, and transferred into an injection vial or ampoule or infusion bottle.

Capsules containing one or more active substances or combinations of active substances can be produced, for example, by mixing active substances with an inert carrier such as lactose or sorbitol and packing them into gelatin capsules. .
Suitable suppositories can be made, for example, by mixing with carriers provided for this purpose, such as natural fats or polyethylene glycols or derivatives thereof.
Excipients that can be used are, for example, water, pharmaceutically acceptable organic solvents such as paraffin (eg petroleum fractions), vegetable oils (eg peanut or sesame oil), mono- or polyfunctional alcohols (eg ethanol or glycerol), carriers For example natural mineral powders (eg kaolin, clay, talc, chalk), synthetic mineral powders (eg highly dispersed silicic acid and silicates), sugars (eg sugarcane sugar, lactose and glucose), emulsifiers (eg sulfite pulp waste liquor, methylcellulose, starch and Polyvinylpyrrolidone) and lubricants such as magnesium stearate, talc, stearic acid and sodium lauryl sulfate.

For oral administration, tablets, of course, apart from the carriers described above, are combined with various additives such as starch, preferably potato starch, gelatin and the like, together with additives such as sodium citrate, calcium carbonate and dicalcium phosphate. May be included. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used simultaneously for the tableting process. In the case of an aqueous suspension, the active substance can be combined with various flavor enhancers or colorants in addition to the excipients described above.
When a compound of formula 1 is used as preferred according to the invention for the treatment of respiratory diseases, it is particularly preferred to use a formulation or pharmaceutical formulation which can be administered by inhalation. Formulations suitable for inhalation include inhalable powders, jet driven metered dose aerosols or inhalable solutions without jetting. Within the scope of the present invention, the term inhalable solution without spraying also includes concentrates or sterilized ready-to-use inhalable solutions. Formulations that can be used within the scope of the present invention are described in detail in the following part of the specification.
Inhalable powders that may be used in accordance with the present invention may comprise 1 either by themselves or in admixture with suitable physiologically acceptable excipients.

When active substance 1 is present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients are used to produce these inhalable powders of the invention Can be: monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, saccharose, maltose) oligo- and polysaccharides (eg dextran), polyhydric alcohols (eg sorbitol, mannitol, xylitol), salts (eg chloride) Sodium, calcium carbonate) or mixtures of these excipients. Preferably, mono- or disaccharides are used, but the use of lactose or glucose is particularly preferred, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is a particularly preferred excipient, but lactose monohydrate is most particularly preferred.

Within the inhalable powders according to the invention, the excipient has a maximum average particle size of up to 250 μm, preferably between 10 and 150 μm, most preferably between 15 and 80 μm. In some cases, it may be appropriate to add a fine excipient fraction having an average particle size of 1-9 μm to the excipient described above. These fine excipients are also selected from the group of possible excipients listed above. Finally, to produce an inhalable powder according to the invention, the finely divided active substance 1 preferably having an average particle size of 0.5 to 10 μm, more preferably 1 to 5 μm, is added to the excipient mixture. Added. Processes for producing the inhalable powders of the present invention by grinding and pulverizing the ingredients together and finally mixing are known in the prior art.
The inhalable powders according to the invention can be administered using inhalers known from the prior art.
The inhaled aerosol-containing propellant according to the invention may comprise Compound 1 dissolved in the propellant gas or in dispersed form. Propellant gases that can be used to produce inhaled aerosols are known from the prior art. Suitable propellant gases are selected from hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as methane, ethane, propane, butane, cyclopropane or fluorinated derivatives of cyclobutane. The above propellant gases can be used on their own or in a mixture. Particularly preferred propellant gases are halogenated alkane derivatives selected from TG134a and TG227 and mixtures thereof.

The jet driven inhalation aerosol may also contain other components such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH adjusters. All these ingredients are known in the art.
The above jet driven inhalation aerosol according to the present invention can be administered using inhalers (MDIs = metered dose inhalers) known in the art.
Furthermore, the active substance 1 according to the invention can be administered in the form of inhalable solutions and suspensions without spraying. The solvent used may be aqueous or alcohol, preferably an ethanol solution. The solvent can be water on itself or a mixture of water and ethanol. The relative proportion of ethanol compared to water is not limited, but the maximum is preferably up to 70% volume, more preferably up to 60% volume and most preferably up to 30% volume. The remainder of the volume consists of water. The solution or suspension containing 1 is adjusted to a pH of 2-7, preferably 2-5, using a suitable acid. The pH can be adjusted with acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid. Preferred inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use an acid that has already formed an acid addition salt with one of the active substances. The organic acid is preferably ascorbic acid, fumaric acid or citric acid. If desired, the above acid mixtures may be used, especially in the case of acids having other properties in addition to their acidic properties, such as flavoring, antioxidants or complexing agents such as citric acid or ascorbic acid. it can. According to the invention, it is particularly preferred to adjust the pH using hydrochloric acid.

If desired, the addition of edetic acid (EDTA) or one of their known salts, sodium edetate, can be removed in these formulations as a stabilizer or complexing agent. Other embodiments may include this compound or these compounds. In a preferred embodiment, the content based on sodium edetate is less than 100 mg / 100 ml, preferably less than 50 mg / 100 ml, more preferably less than 20 mg / 100 ml. Usually, inhalable solutions with a sodium edetic acid content of 0 to 10 mg / 100 ml are preferred.
Co-solvents and / or other excipients can be added to the inhalable solution without spraying. Preferred cosolvents are those containing hydroxy groups or other polar groups such as alcohol-especially isopropyl alcohol, glycol-especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohol and polyoxyethylene fatty acid esters. . The terms excipients and additives in this context refer to some pharmacologically acceptable substance that is not an active substance, but it is physiological, in order to improve the qualitative properties of the active substance formulation. Can be clearly expressed using the active substance in a suitable solvent. Preferably, these substances do not have a pharmacological effect, or at least a suitable pharmacological effect in connection with the desired treatment. Excipients and additives include, for example, surfactants such as soy lecithin, oleic acid, sorbitan esters such as polysorbate, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives (final pharmaceuticals). Ensuring or extending the shelf life of the formulation), flavoring, vitamins and / or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.

Preferred excipients include antioxidants such as ascorbic acid, for example, but without already using it to adjust pH, vitamin A, vitamin E, tocopherol and similar vitamins and provitamins generated in the human body. ing.
Preservatives can be used to protect the formulation from contamination with pathogens. Suitable preservatives are those known in the art, in particular cetylpyridium chloride, benzalkonium chloride or benzoic acid or benzoates, such as sodium benzoate, in concentrates known from the prior art. Said preservative is preferably present in a concentration of up to 50 mg / 100 ml, more preferably between 5 and 20 mg / 100 ml.
A preferred formulation contains only benzalkonium chloride and sodium edetate in addition to solvent water and active substance 1 . In another preferred embodiment, no sodium edetate is present.
The dose of the compound according to the invention is necessarily high and depends on the method of administration and the disease being treated. When administered by inhalation, compounds of formula 1 are characterized by high efficacy, even at doses in the μg range. The compounds of formula 1 can also be used effectively above the μg range. The dose may then be in the milligram range, for example.

活性物質を、水において、それ自身のｐＨで又は場合によりｐＨ５．５〜６．５で溶解し及び塩化ナトリウムを、添加して、それを等張にした。得られた溶液を、ろ過しピロゲンから離し及びろ液を、アンプル内に無菌状態下で移送し、それを、次いで、殺菌し及び融解によりシールした。アンプルは、５ｍｇ、２５ｍｇ及び５０ｍｇの活性物質を含んだ。 In another aspect, the invention relates to a pharmaceutical formulation as described above, which is characterized in that it comprises a compound of formula 1 such as a particularly preferred pharmaceutical formulation as described above for use by inhalation.
The following formulation examples illustrate the invention without limiting its scope:
A) Ampoule solution

The active substance was dissolved in water at its own pH or optionally at pH 5.5-6.5 and sodium chloride was added to make it isotonic. The resulting solution was filtered off the pyrogen and the filtrate was transferred under aseptic conditions into an ampoule which was then sterilized and sealed by thawing. Ampoules contained 5 mg, 25 mg and 50 mg of active substance.

サスペンションを、計量値を有する従来のエアロゾル容器内に注いだ。好ましくは、５０μｌのサスペンションを、一吹きで供給した。活性物質はまた、所望なら、高投与量において供給することができる。
Ｃ）定量エアロゾル（溶液）

溶液を、個々の構成物質を混合することにより従来の方法において製造した。 B) Quantitative aerosol (suspension)

The suspension was poured into a conventional aerosol container with a metered value. Preferably, 50 μl of suspension was supplied in one blow. The active substance can also be supplied in high doses if desired.
C) Quantitative aerosol (solution)

Solutions were prepared in a conventional manner by mixing the individual constituents.

吸入可能粉末を、個々の構成物質を混合することにより従来の方法において製造した。 D) Suctionable powder

Inhalable powders were produced in a conventional manner by mixing the individual constituents.

Claims (14)

It may optionally be in the form of individual enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, or in some cases Compounds of general formula 1 which may be in the form of solvates and / or hydrates:

(Wherein n represents 1 or 2;
A represents a double bond group selected from — (C═O) —, —S (═O) —, —S (═O) ₂ — and —C (R ⁴ R ⁵ ) —;
B represents —O—, —NR ⁶ , —CH ₂ —, —S—CR ⁷ R ⁸ —, —NR ⁶ —CR ⁷ R ⁸ —, —CH ₂ —CR ⁷ R ⁸ —, —O—CR ^9. R ¹⁰ - and denotes a double-bonded group selected from -CH = CH-;
R ¹ and R ² may be the same or different and represent hydrogen, C _1-4 alkyl, halogen, OH or —O—C _1-4 alkyl;
R ³ is hydrogen, C _1-4 alkyl, OH, halogen, —O—C _1-4 alkyl, —COOH, —COO—C _1-4 alkyl, —O—C _1-4 alkylene-COOH or —O. -C _1-4 alkylene-CO-O-C _1-4 alkyl is shown;
R ⁴ and R ⁵ may be the same or different and are hydrogen, C _1-4 alkyl, OH, halogen, —O—C _1-4 alkyl, —COOH or —COO—C _1-4 alkyl. Indicates;
R ⁶ represents hydrogen or C _1-4 alkyl;
R ⁷ and R ⁸ may be the same or different and represent hydrogen or C _1-4 alkyl;
R ⁹ and R ¹⁰ may be the same or different and represent C _1-4 alkyl). n represents 1 or 2;
A represents a double bond group selected from — (C═O) —, —S (═O) ₂ —, and —C (R ⁴ R ⁵ ) —;
B represents —O—, —NR ⁶ —, —CH ₂ —, —S—CR ⁷ R ⁸ —, —NR ⁶ —CR ⁷ R ⁸ —, —CH ₂ —CR ⁷ R ⁸ —, —O—CR. ⁹ represents a double bond group selected from R ¹⁰ -and -CH = CH-;
R ¹ and R ² may be the same or different and represent hydrogen, methyl, ethyl, propyl, fluorine, chlorine, bromine, OH, methoxy or ethoxy;
R ³ is hydrogen, methyl, ethyl, propyl, fluorine, chlorine, bromine, OH, methoxy, ethoxy, —COOH, —COO methyl, —COO ethyl, —O—CH ₂ —COOH, —O—CH ₂ —COO. - methyl, -O-CH ₂ -COO- _{ethyl, -O-CH 2 -CH 2 -COOH} , -O-CH 2 -CH 2 -COO- methyl, -O-CH ₂ -CH ₂ -COO- ethyl, _{-O-CH 2 -CH 2 -CH 2} -COOH, -O-CH 2 -CH 2 -CH 2 -COO- methyl or _{-O-CH 2 -CH 2 -CH 2} -COO- ethyl;
R ⁴ and R ⁵ may be the same or different and represent hydrogen, methyl, ethyl, OH, fluorine, chlorine, —COOH, —COO methyl or —COO ethyl;
R ⁶ represents hydrogen, methyl, ethyl or propyl, preferably hydrogen;
R ⁷ and R ⁸ may be the same or different and represent hydrogen, methyl, ethyl or propyl;
R ⁹ and R ¹⁰ may be the same or different and represent methyl, ethyl or propyl;
It may optionally be in the form of individual enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmaceutically acceptable acids, or in some cases The compound of formula 1 according to claim 1, which may be in the form of a solvate and / or hydrate of n represents 1 or 2;
A represents a double bond group selected from — (C═O) —, —S (═O) ₂ —, and —C (R ⁴ R ⁵ ) —;
B represents —O—, —NR ⁶ —, —CH ₂ —, —S—CR ⁷ R ⁸ —, —NR ⁶ —CR ⁷ R ⁸ —, —CH ₂ —CR ⁷ R ⁸ —, —O—CR. ⁹ represents a double bond group selected from R ¹⁰ -and -CH = CH-;
R ¹ and R ² may be the same or different and represent hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy or ethoxy;
R ³ is hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy, ethoxy, —COOH, —COO methyl, —COO ethyl, —O—CH ₂ —COOH, —O—CH ₂ —COO-methyl, — O-CH ₂ -COO- _{ethyl, -O-CH 2 -CH 2 -COOH} , -O-CH 2 -CH 2 -COO- methyl or -O-CH ₂ -CH ₂ -COO- ethyl;
R ⁴ and R ⁵ may be the same or different and represent hydrogen, methyl, ethyl, —COOH, —COO methyl or —COO ethyl;
R ⁶ represents hydrogen, methyl or ethyl;
R ⁷ and R ⁸ may be the same or different and represent hydrogen, methyl or ethyl, preferably hydrogen or methyl;
R ⁹ and R ¹⁰ may be the same or different and represent methyl or ethyl, preferably methyl,
It may optionally be in the form of individual enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, or in some cases The compound of formula 1 according to claim 1 or 2, which may be in the form of a solvate and / or hydrate of n represents 1 or 2;
A represents a double bond group selected from — (C═O) —, —S (═O) ₂ —, and —C (R ⁴ R ⁵ ) —;
B is, -O -, - NH -, - CH 2 -, - S-CH 2 -, - NH-CH 2 -, - CH 2 -CH 2 -, - O-CR 9 R 10 - and -CH = A double bond group selected from CH-;
R ¹ and R ² may be the same or different and represent hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy or ethoxy;
R ³ is hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy, ethoxy, —COOH, —COO methyl, —COO ethyl, —O—CH ₂ —COOH, —O—CH ₂ —COO-methyl, — O-CH ₂ -COO- _{ethyl, -O-CH 2 -CH 2 -COOH} , -O-CH 2 -CH 2 -COO- methyl or -O-CH ₂ -CH ₂ -COO- ethyl;
R ⁴ and R ⁵ may be the same or different and represent hydrogen, methyl, ethyl, —COOH, —COO methyl or —COO ethyl;
R ⁹ and R ¹⁰ may be the same or different and are preferably the same and represent methyl or ethyl, preferably methyl,
It may optionally be in the form of individual enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, or in some cases The compound of formula 1 according to any one of claims 1 to 3, which may be in the form of a solvate and / or a hydrate. n represents 1 or 2;
A represents a double bond group selected from — (C═O) — and —S (═O) ₂ —;
B is, -O -, - NH -, - CH 2 -, - S-CH 2 -, - NH-CH 2 -, - CH 2 -CH 2 -, - O-CR 9 R 10 - and -CH = A double bond group selected from CH-;
R ¹ and R ² may be the same or different and represent hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy or ethoxy;
R ³ is hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy, ethoxy, —COOH, —COO methyl, —COO ethyl, —O—CH ₂ —COOH, —O—CH ₂ —COO-methyl, — O-CH ₂ -COO- _{ethyl, -O-CH 2 -CH 2 -COOH} , -O-CH 2 -CH 2 -COO- methyl or -O-CH ₂ -CH ₂ -COO- ethyl;
R ⁹ and R ¹⁰ may be the same or different and are preferably the same and represent methyl or ethyl, preferably methyl,
It may optionally be in the form of individual enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmacologically acceptable acids, or in some cases The compound of formula 1 according to any one of claims 1 to 4, which may be in the form of a solvate and / or a hydrate. R ¹ and R ² may be the same or different and represent hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy or ethoxy;
R ³ represents hydrogen,
It may optionally be in the form of individual enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmaceutically acceptable acids, or in some cases 6. The compound of formula 1 according to any one of claims 1 to 5, which may be in the form of a solvate and / or hydrate. R ¹ and R ² may be the same or different and represent hydrogen, methyl, fluorine, chlorine or methoxy;
R ³ may be the same or different and represents hydrogen, methyl, fluorine, chlorine or methoxy;
It may optionally be in the form of individual enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmaceutically acceptable acids, or in some cases 6. The compound of formula 1 according to any one of claims 1 to 5, which may be in the form of a solvate and / or hydrate. R ³ is methyl, ethyl, fluorine, chlorine, OH, methoxy, ethoxy, —COOH, —COO methyl, —COO ethyl, —O—CH ₂ —COOH, —O—CH ₂ —COO-methyl, —O—. CH ₂ -COO- _{ethyl, -O-CH 2 -CH 2 -COOH} , a -O-CH ₂ -CH ₂ -COO- methyl or -O-CH ₂ -CH ₂ -COO- ethyl shown,
It may optionally be in the form of individual enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmaceutically acceptable acids, or in some cases 6. The compound of formula 1 according to any one of claims 1 to 5, which may be in the form of a solvate and / or hydrate. R ³ is methyl, ethyl, OH, methoxy, ethoxy, —O—CH ₂ —COOH, —O—CH ₂ —COO-methyl or —O—CH ₂ —COO-ethyl, preferably OH, methoxy or ethoxy Showing,
It may optionally be in the form of individual enantiomers, individual enantiomers or racemic mixtures, optionally in the form of acid addition salts with pharmaceutically acceptable acids, or in some cases 6. The compound of formula 1 according to any one of claims 1 to 5, which may be in the form of a solvate and / or hydrate.   Hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, 10. The form of one of acid addition salts with pharmacologically acceptable acids selected from hydrooxalates, hydrosuccinates, hydrobenzoates and hydro-p-toluenesulfonates. A compound of formula 1 as described in General formula R-1:

11. The compound of formula 1 according to any one of claims 1 to 10, in the form of the R-enantiomer of   The compound of general formula 1 according to any one of claims 1 to 11 as a pharmaceutical composition.   Use of a compound of general formula 1 according to any one of claims 1 to 12 for the manufacture of a pharmaceutical composition for the treatment of respiratory diseases.   A pharmaceutical formulation comprising a compound of formula 1 according to any one of claims 1-12.