KR20020089372A - Derivatives of quinoline as alpha-2 antagonists - Google Patents

Abstract

It is an object of the present invention to provide antagonists of alpha-2 adrenoreceptors in which alpha-2 antagonists are useful in the treatment of diseases and conditions of the peripheral and central nervous system. Accordingly, it is an object of the present invention to provide compounds which are used as alpha-2 antagonists in the treatment of mammals, including humans and animals.

Another object of the present invention is to provide compounds useful as selective alpha-2C antagonists in the treatment of various diseases and conditions of the central nervous system where alpha-2C antagonists are useful.

Description

[0002] DINIVATIVES OF QUINOLINE AS ALPHA-2 ANTAGONISTS AS AN ALP-

Several compounds that exhibit alpha adrenergic activity are well known in the literature. These compounds can be used in the treatment of various areas of the peripheral nervous system and the central nervous system (CNS) of various diseases and conditions.

Alpha adrenergic receptors are classified as alpha-1 and alpha-2 adrenoceptors. These are further subdivided into subtypes. Thus, the alpha-2 adrenoreceptors in the human body are subdivided into pharmacological subtypes known as alpha-2A, alpha-2B and alpha-2C adrenoreceptors. The fourth subtype, alpha-2D, is known in rats, cows and pigs, which corresponds to alpha-2A in the human body. These subtypes have a significant distribution in human and animal tissues. For example, alpha-2C adrenoceptors are enriched in the CNS and appear to play a role in the regulation of several CNS-mediated behaviors and responses.

Non-specific compounds and compounds specific to certain alpha-2 subtypes are already known in any of the alpha-2 subtypes mentioned above. For example, atipamozole is a nonspecific alpha-2 antagonist. Atipamozole is described, for example, in EP-A-183 492 (cf. P 13, compound XV) and Haapalinna et al., Naunyn-Schimiedeberg's Arch. Pharmacol. Vol. 356, 1997, p. 570-582). U.S. Patent No. 5,902,807 describes compounds that are selective antagonists to the alpha-2C subtype and can be used in the treatment of psychiatric disorders such as mental disorders induced by stress. Such compounds include, for example, MK-912 and BAM-1303. Furthermore, WO-A 99 28300 describes substituted imidazole derivatives having agonistic activity at alpha-2B or 2B / 2C adrenoreceptors. The contents of all of the above cited documents are hereby incorporated by reference.

As a quinoline derivative, Medicinskaja parazitologija I parazitarnye bolezni, vol. 5, 1991, 55-7 (Mikhailitsyn F. S. et al.) And J. Med. Chem., Vol. 20 (8), 1977, 987-996 (Cain F. C. et al.) Describe acridine derivatives as, for example, anticancer agents and / or repellents. In addition, publications by Adams et al in 1985 (Mol. Pharm. 27, 480-491) show that diquinolines, diacridines and many monoacids in the rat brain alpha-1, alpha-2 and beta-adrenoreceptors Lt; RTI ID = 0.0 > of the < / RTI >

The present invention relates to therapeutically active quinoline derivatives, their pharmaceutically acceptable salts and esters thereof and their use as alpha-2 antagonists.

Figure 1 shows the effect of atipamole and compound 1 on dexmedetomidine-induced hypolocomotion.

Figure 2 shows the effect of atipamole and compound 1 in a forced swimming test in Balb / c mice.

The present invention provides compounds of formula I, their pharmaceutically acceptable salts and esters.

From here,

R ₁ is H or (C ₁ -C ₆ ) alkyl;

Each R ₂ is independently OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₁ -C ₆₎ alkoxy, halo (C ₁ -C ₆₎ alkyl, NO ₂ , NH _2, mono- or di - (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl, -S- or hydroxy (C ₁ -C ₆₎ alkyl;

A is a benzene ring or (C5-C7) cycloalkyl;

When A is benzene sun dog, each R3 is independently OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₁ -C ₆₎ alkoxy, halo - (C ₁ -C ₆₎ alkyl, NO _2, NH _2, mono- or di - (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl, -CO, mono- or di - (C ₁ -C ₆₎ - alkyl Carbamoyl, (C ₁ -C ₆ ) alkyl-S-, hydroxy (C ₁ -C ₆ ) alkyl, or NH ₂ -CO-;

When A is (C ₅ -C ₇₎ cycloalkyl, each R ₃ is independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, mono-or di - (C ₁ -C ₆₎ alkylamino, or hydroxy (C ₁ -C ₆₎ alkyl;

R ₄ and R ₅ have the following structure together with the N-atom to which they are bonded.

Wherein X is O or = NR < _{6 &} gt ;. R ₆ is selected from the group consisting of H, NH ₂ , (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, CN- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy- C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkyl, -CO-, -CO- NH _2, mono- or di - (C ₁ -C ₆₎ alkyl, carbamoyl, hydroxy (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆₎ cycloalkyl, phenyl, naphthyl and naphthyl or benzyl, where the above-mentioned phenyl, naphthyl, or benzyl are independently OH, _{halogen, NO 2, NH 2, (} C 1 - C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, mono-or di - (C ₁ -C ₆₎ alkylamino, halo or - (C ₁ -C ₆₎ optionally substituted with 1 to 3 substituents selected from alkyl .

Or R < ₄ > and R < ₅ > together with the N-atom to which they are attached form the following structure.

Wherein n is 1 or 2; R ₆ is as defined above; r is 0 to 3;

Or R ₄ and R ₅ together with the N atom to which they are attached form a 1-imidazolyl, 1-imidazolinyl, or 1-triazolyl, which are each independently (C ₁ -C ₆ ) alkyl or the substituents R ₇ NH ₂ in which 1 to 3 may be optionally substituted;

Or one of R ₄ and R ₅ is -SO ₂ R ₈ and the remainder of R ₄ and R ₅ is H or (C ₁ -C ₆ ) alkyl; R ₈ is (C ₁ -C ₆₎ alkyl, phenyl, naphthyl and naphthyl or benzyl, where the above-mentioned phenyl, naphthyl, or benzyl are independently OH, _{halogen, NO 2, NH 2, (} C 1 -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, or mono- or di - (C ₁ -C ₆₎ may be optionally substituted with 1 to 3 R ₉ substituents selected from alkylamino;

Ra and Rb are independently H, OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₂ -C ₆₎ alkynyl, (C ₁ -C ₆₎ alkoxy, (C ₁ -C ₆ ) alkyl, NO ₂ , NH ₂ , mono- or di- (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₆ ) alkyl-S- or CN;

Or R <a> and R <b> together with the carbon to which they are attached form a fused benzene ring. Independently ring is condensed benzene OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₁ -C ₆₎ alkoxy, halo - (C ₁ -C ₆₎ alkyl, NO _2, NH _2, mono- or di - (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl, -CO-, mono- or di - (C ₁ -C ₆₎ - alkyl carbamoyl, ( C ₁ -C ₆₎ alkyl, -S-, hydroxy (C ₁ -C ₆₎ alkyl, or is a NH ₂ -CO- the substituents R'3 optionally may be substituted from 1 to 3;

Or Ra and Rb may be condensed with a 5- to 7-membered carbocyclic ring together with the carbon to which they are attached. Are each independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, mono-or di - (C ₁ -C ₆₎ alkyl amino, halo (C ₁ -C ₆₎ alkyl Lt; RTI ID = 0.0 &gt; R10, &lt; / RTI &gt;

Or Ra and Rb may form bicyclo [2,2,1] -heptane fused with the carbon ring atoms to which they are attached, which are independently OH, halogen, (C ₁ -C ₆ ) alkyl, or C ₁ -C ₆ ) alkoxy;

Or Ra and Rb may form a ring heteroatom = NR a 5-or 6-membered heterocyclic ring condensed with ₁₁ with the carbon ring atoms to which they are bonded, they are optionally 1 to 3 chihoen with R ₁₀ defined before Can be; R ₁₁ is H or (C ₁ -C ₆ ) alkyl or is each independently selected from the group consisting of OH, halogen, NO ₂ , NH ₂ , (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, di - (C ₁ -C ₆₎ may be arbitrarily substituted with 1 to 3 alkyl amino substituents R _11;.

m is 0 to 3; ego,

t is from 0 to 3;

Compounds of formula I may be used in the preparation of therapeutic agents for the treatment of diseases or conditions in which alpha-2 antagonists are effective.

The following subgroups (1) to (18) of the compounds of formula I may be used alone or in combination with one another.

(1) A is a benzene ring;

(2) A is (C ₅ -C ₇₎ cycloalkyl;

(3) Ra and Rb are independently H, OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₂ -C ₆₎ alkynyl, (C ₁ -C ₆ ) alkoxy, halo (C ₁ -C ₆₎ alkyl, NO _2, NH _2, mono- or di - (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl, -S-, or CN; For example, H, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₂ -C ₆₎ alkynyl, (C ₁ -C ₆₎ alkoxy, or halo (C ₁ - C ₆ ) alkyl; Preferably H, halogen, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy group which, more preferably, H, or (C ₁ -C ₃₎ alkyl, above where (C ₁ - C ₃ ) alkyl includes straight chain or branched alkyl groups of up to 3 carbon atoms.

(4) Ra and Rb form a condensed benzene ring together with the carbon atom to which they are bonded. They are each independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₁ -C ₆₎ alkoxy, halo (C ₁ -C ₆₎ alkyl, NO _2, NH ₂ , mono-or di- (C ₁ -C ₆ ) alkylimino, (C ₁ -C ₆ ) alkyl-S- or hydroxy- (C ₁ -C ₆ ) alkyl, preferably OH, C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl or (C ₁ -C ₆₎ alkoxy, and, more preferably, halogen, (C ₁ -C ₆₎ alkyl or (C ₁ -C ₆ ) is selected from alkoxy substituent (s) R _'3 may be arbitrarily substituted with 1 to 3;

(5) Ra and Rb may be condensed with a 5- to 7-membered carbocyclic ring together with the carbon ring atom to which they are bonded. Are each independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, mono-or di - (C ₁ -C ₆₎ alkyl amino, halo (C ₁ -C ₆₎ alkyl Lt; / RTI &gt; may be substituted by 1 to 3 substituents R &lt; ₁₀ &gt; Preferably (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy; More preferably (C ₁ -C ₆ ) alkyl;

(6) Ra and Rb are a bicyclo [2,2,1] condensed with a carbon ring atoms to which they are bonded - may form a heptane, all of which are independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, or (C ₁ -C ₆₎ alkoxy optionally substituted with 1 to 3 substituents;

(7) Ra and Rb may form a ring heteroatom = NR a 5-or 6-membered heterocyclic ring condensed with ₁₁ with the carbon ring atoms to which they are bonded, they are optionally 1 to R ₁₀ defined by the front It can be tripled; R ₁₁ is H or (C ₁ -C ₆ ) alkyl or is each independently selected from the group consisting of OH, halogen, NO ₂ , NH ₂ , (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, di - (C ₁ -C ₆₎ alkyl is an amino substituent R ₁₂ may be optionally substituted with 1 to 3;

(8) Ra and Rb together with the N-atom form 1-piperazinyl. This may have 4-substituents as R ₆ as defined above. R ₆ is _{NH 2, (C 1 -C 6} ) alkyl, (C ₂ -C ₆₎ alkenyl, CN- (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy -CO- (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkyl, -CO-, -CO- NH _2, mono- or di - (C ₁ -C ₆₎ alkyl, carbamoyl, hydroxy (C ₁ -C ₆₎ alkyl , (C ₃ -C ₆₎ cycloalkyl, phenyl, naphthyl or benzyl, and naphthyl, all of which are (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl ,, hydroxy (C ₁ -C ₆₎ alkyl , (C ₃ -C ₆ ) cycloalkyl, more preferably (C ₁ -C ₆ ) alkyl;

(9) Ra and Rb together with the N-atom form a morpholino ring;

(10) Ra and Rb together with the N-atom form a 1-piperidinyl or 1-pyrrolidinyl ring. These may optionally be substituted with R ₆ as defined hereinbefore. R ₆ is (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, CN- (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy -CO- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆₎ alkyl, -CO-, -CO- NH _2, mono- or di - (C ₁ -C ₆₎ alkyl, carbamoyl, hydroxy (C ₁ -C ₆₎ alkyl, (C ₃ -C ₆₎ cycloalkyl, phenyl, naphthyl and naphthyl or benzyl, preferably (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl ,, hydroxy (C ₁ -C ₆₎ alkyl, (C ₃ -C ₆ ) cycloalkyl, more preferably (C ₁ -C ₆ ) alkyl;

(11) Ra and Rb together with the N-atom form a 1-imidazolyl, 1-imidazolinyl or 1-triazolyl ring. These may be optionally substituted with R ₇ as defined hereinbefore. R ₇ may be substituted, for example, by 1 to 3 substituents with (C ₁ -C ₆ ) alkyl or NH ₂ ; Ra and Rb together with the N-atom form 2-amino-imidazol-1-yl or 2-amino-imidazolin-1-yl;

(12) R ₄ and R ₅ is one of -SO ₂ R _8, and, R ₄ and R ₅ of the other is H, or (C ₁ -C ₆₎ alkyl; R ₈ is (C ₁ -C ₆₎ alkyl, phenyl, naphthyl and naphthyl or benzyl, where the above-mentioned phenyl, naphthyl, or benzyl is independently OH, _{halogen, NO 2, NH 2, C} 1 -C 6 respectively ) alkyl, (C ₁ -C ₆₎ alkoxy, or mono- or di - (C ₁ -C ₆₎ may be optionally substituted with 1 to 3 R ₉ substituents selected from alkylamino;

(13) m is 0 to 3; Preferably 0 or 1; More preferably 0;

(14) t is 0 to 3; Preferably 0 or 2; More preferably 0 or 1, most preferably 0; And / or

(15) R ₁ is H;

(16) R ₁ is (C ₁ -C ₆ ) alkyl;

(17) R ₂ is independently selected from OH, halogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkoxy, halo (C ₁ -C ₆ ) NO _2, NH _2, mono- or di - (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl, -S- or hydroxy (C ₁ -C ₆₎ alkyl; (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or hydroxy (C ₁ -C ₆ ) alkyl; More preferably (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkoxy; And / or

(18) R ₃ is independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₁ -C ₆₎ alkoxy, halo - (C ₁ -C ₆₎ alkyl , NO _2, NH _2, mono- or di - (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl, -CO, mono- or di - (C ₁ -C ₆₎ - alkyl carbamoyl, (C ₁ -C ₆₎ alkyl, -S-, hydroxy (C ₁ -C ₆₎ alkyl, or NH ₂ -CO-; (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkoxy, halo - (C ₁ -C ₆ ) alkyl; More preferably halogen, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkoxy.

A possible subgroup of compounds of formula I are compounds of formula IA.

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₁₀ , m and t are as defined above; i is from 1 to 3 and j is from 0 to 4.

Another possible subgroup of compounds of formula I are compounds of formula IB.

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R a, R b, m and t are as defined above; Ra and Rb are as H, OH, halogen, (C ₁ -C ₆₎ independently alkyl, (C ₂ -C ₆₎ alkenyl, (C ₂ -C ₆₎ alkynyl (C ₁ -C ₆₎ alkoxy, halo - (C ₁ -C ₆ ) alkyl, NO ₂ , NH ₂ , mono- or di- (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₆ ) alkyl-S- or CN; Alternatively, Ra and Rb may form a 5- to 7-membered ring fused together with the carbon ring atoms to which they are attached. The ring may be optionally substituted with 1 to 3 substituents R &lt; ₁₀ &gt;. R ₁₀ is independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, mono-or di - (C ₁ -C ₆₎ alkylamino or hydroxy (C ₁ -C ₆ ) Alkyl.

Another possible sub-group of formula I is a compound of formula IC.

Wherein R ₁ , R ₂ , R ₃ , R 4, R ₅ , R ₁₀ , R ₁₁ , m and t are as defined above; i is from 1 to 2 and j is from 0 to 3.

Another possible subgroup of compounds of formula I are compounds of formula ID.

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , m and t are as defined above; p is from 0 to 3; Preferably m is 1 and the R ₃ is (C ₁ -C ₆₎ alkoxy.

In the structural formulas I, IA, IB, IC or ID, R ₄ and R ₅ , together with the N atom to which they are attached, form the following structural formula.

Wherein X is = NR &lt; ₆ &gt;; R ₆ is as defined in formula I; Preferably (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy (C ₁ -C ₆ ) alkyl, or (C ₃ -C ₆ ) cycloalkyl; More preferably (C ₁ -C ₆ ) alkyl.

Another aspect of the present invention is to provide a novel compound, a pharmaceutically acceptable salt thereof, of structural formula II.

In this formula,

R ₁ is H or (C ₁ -C ₆ ) alkyl;

Each R ₂ is independently OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₁ -C ₆₎ alkoxy, halo - (C ₁ -C ₆₎ alkyl, NO _2, NH _2, mono- or di - (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl, -S-, or hydroxy (C ₁ -C ₆₎ alkyl;

A is a benzene ring or (C ₅ -C ₇₎ cycloalkyl;

When A is a benzene ring, each R ₃ is independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₁ -C ₆₎ alkoxy, halo - (C ₁ - C ₆₎ alkyl, NO _2, NH _2, mono- or di - (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl, -CO-, mono- or di - (C ₁ -C ₆₎ alkyl carbamoyl, (C ₁ -C ₆₎ alkyl, -S-, hydroxy is hydroxy (C ₁ -C ₆₎ alkyl, NH ₂ -CO-.;

When A is a (C ₅ -C ₇₎ cycloalkyl, each R ₃ is independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, mono-or di - (C ₁ -C ₆₎ alkyl amino or hydroxy (C ₁ -C ₆₎ alkyl;

R &lt; ₄ &gt; and R &lt; ₅ &gt; together with the N-atom to which they are attached form a group of the formula:

Wherein X is O or = NR &lt; _{6 &} gt ;; R ₆ is H, OH, NH 2, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, CN- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkyl, -CO-, -CO- NH _2, mono- or di - (C ₁ -C ₆₎ alkyl, carbamoyl, hydroxy (C ₁ -C ₆₎ alkyl, (C ₃ -C ₆₎ cycloalkyl, or benzyl, the above-mentioned benzyl here are each independently OH, _{halogen, NO 2, NH 2, (} C 1 -C 6) alkyl, (C ₁ - C ₁ -C ₆ ) alkoxy, mono- or di- (C ₁ -C ₆ ) alkylamino, or halo - (C ₁ -C ₆ ) alkyl;

Or R4 and R5 together with the N-atom to which they are attached form the following group.

Wherein n is 1 or 2; R ₆ is as defined above; r is 0 to 3;

Or R ₄ and R ₅ together with the N atom to which they are attached form a 1-imidazolyl, 1-imidazolinyl, or 1-triazolyl. Each of which may be each independently (C ₁ -C _{6) 1} to 3 substituents selected from optionally alkyl or NH ₂ R ₇ optionally substituted;

Ra and Rb is a H, OH, halogen, (C ₁ -C ₆₎ independently alkyl, (C ₂ -C ₆₎ alkenyl, (C ₂ -C ₆₎ alkynyl, (C ₁ -C ₆₎ alkoxy, (C ₁ -C ₆ ) alkyl, NO ₂ , NH ₂ , mono- or di- (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₆ ) alkyl-S- or CN;

Or Ra and Rb together with the carbon to which they are attached form a condensed benzene ring. They are each independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₁ -C ₆₎ alkoxy, halo (C ₁ -C ₆₎ alkyl, NO _2, NH _2, mono- or di - (C ₁ -C ₆₎ alkyl is agate, (C ₁ -C ₆₎ alkyl, -CO-, mono- or di - (C ₁ -C ₆₎ alkyl carbamoyl, (C ₁ - C ₆₎ alkyl, -S- hydroxy - (C ₁ -C ₆₎ it may be substituted with alkyl or NH ₂ -CO- in which the substituents R'3 optionally 1 to 3.

Or Ra and Rb may be condensed with a 5- to 7-membered carbocyclic ring together with the carbon to which they are attached. Are each independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, mono-or di - (C ₁ -C ₆₎ alkyl amino, halo (C ₁ -C ₆₎ alkyl , hydroxy (C ₁ -C ₆₎ alkyl may be substituted with substituents R ₁₀ optionally 1 to 3;

Or Ra and Rb may form bicyclo [2,2,1] -heptane fused with the carbon ring atoms to which they are attached, which are independently OH, halogen, (C ₁ -C ₆ ) alkyl, or C ₁ -C ₆ ) alkoxy;

Or Ra and Rb may form a ring heteroatom = NR a 5-or 6-membered heterocyclic ring condensed with ₁₁ with the carbon ring atoms to which they are bonded, they are optionally 1 to 3 chihoen with R ₁₀ defined before Can be; R ₁₁ is H or (C ₁ -C ₆ ) alkyl or is each independently selected from the group consisting of OH, halogen, NO ₂ , NH ₂ , (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, di - (C ₁ -C ₆₎ alkyl is an amino substituent R ₁₂ may be optionally substituted with 1 to 3;

m is 0 to 3; And

t is from 0 to 3;

However, under the following conditions.

a) when A is a benzene ring, m is 0 or 1, R ₁ is H, R ₃ is Cl or NO ₂ , Ra and Rb together with the carbon ring atom to which they are attached form a fused benzene ring, X is NR _6, R ₆ is _{H, -CH 3, -CH 2 CH} 3, not a -COCH _3, or -CO-NH _2.;

b) when A is a benzene ring, Ra and Rb are not simultaneously H;

c) when A is a benzene ring, m is 1, t is 0, R1 is H, Ra and Rb together with the carbon ring atom to which they are attached form a fused benzene ring, which ring may optionally be substituted with Br. X is O, R ₃ is not NO ₂ or -OCH _3.

d) when A is a benzene ring, m is ㅐ, t is 0 and R ₁ is H and Ra and Rb are unsubstituted benzene rings condensed with the carbon to which they are attached, X is not O;

e) the compound is 4- [4 - [(6-chloro-2-methyl-4-quinolinyl) amino] phenyl] Amino-4- [4 - [(3-chloro-4- (1 H-imidazol-1-ylmethoxy) Phenyl] amino] -7-methoxy-6-nitro-3-quinolinecarbonitrile.

A possible subgroup of compounds of formula II are the compounds of formula IIA, their pharmaceutically acceptable salts and esters.

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₁₀ , m and t are as described for formula II, i is 1 to 3; j is 0 to 4; For example,

i is 2, j is 0 or 1 and R ₁₀ is (C ₁ -C ₃ ) alkyl, wherein (C ₁ -C ₃ ) alkyl includes a straight chain or branched alkyl group of up to 3 carbon atoms.

Where m is 0 or 1, R ₃ is (C ₁ -C ₃₎ alkyl or halogen, where the (C ₁ -C ₃₎ alkyl includes straight-chain or branched alkyl group of up to 3 carbon atoms.

Wherein the compound is

Phenyl] - (1, 2,3, 4-tetrahydroacridin-9-yl) amine,

2-4- [4- (1,2,3,4-tetrahydroacridin-9-yl) aminophenyl] pyrazin- 1 -yl ethanol,

Phenyl] - (2-methyl-1,2,3,4-tetrahydroacridin-9-yl) amine,

(8-fluoro-l, 2,3,4-tetrahydroacridin-9-yl) - [4- (4-methylpiperazin- 1- yl) phenyl]

Yl] phenyl] (2,3-dimethyl-1,2,3,4-tetrahydroacridin-9-yl) amine,

Yl) phenyl] - (7,8,9,10-tetrahydro-6H-cyclohepta [b] quinolin-11-yl) amine, or

[4- (4-methylpiperazin-1-yl) phenyl] - (1,1,3,3-tetramethyl-l, 2,3,4-tetrahydroacridin-9-yl) amine.

Another possible sub-group of compounds of formula II is a compound of formula IB, a pharmaceutically acceptable salt or ester thereof.

Wherein A, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , m and t are as described for formula II;

Ra and Rb are independently H, OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₂ -C ₆₎ alkynyl, (C ₁ -C ₆₎ alkoxy, halo (C ₁ -C ₆₎ alkyl, NO _2, NH _2, mono- or di - (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl, or -S-, or CN; Or Ra and Rb together with the carbon ring atoms to which they are attached, form a 5- to 7-membered ring may form a click sayi carbonyl source, all of which are independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, mono-or di - (C ₁ -C ₆₎ may be alkylamino, or hydroxy (C ₁ -C ₆₎ alkyl substituted with R _10, optionally substituted with 1 to 3; For example,

Wherein A is a benzene ring; or

Wherein m is 0 or 1; or

Wherein R ₃ is (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy; or

Here, the Ra and Rb are independently H or (C ₁ -C ₃₎ alkyl, where the (C ₁ -C ₃₎ alkyl includes straight-chain or branched alkyl group of up to 3 carbon atoms; or

Wherein A is a 6-membered carbocyclic ring and Ra and Rb form a 5-to 7-membered carbocyclic ring condensed with the carbon atom to which they are attached. Wherein the carbocyclic ring is optionally substituted with one to three substituents independently selected from OH, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or hydroxy (C ₁ -C ₆ ) &Lt; / RTI &gt; Or the following compounds.

(3-ethyl-2,8-dimethylquinolin-4-yl- [4- (4-methylpiperazin- 1- yl) phenyl]

(2-methylquinolin-4-yl) - [4- (4-methylpiperazin-1-yl) phenyl]

(3-ethyl-2,6-dimethylquinolin-4-yl) - [4-

(3-ethyl-6-methoxy-2-methylquinolin-4-yl) - [4-

(3-ethyl-2-methylquinolin-4-yl) - [4- (4-methylpiperazin- 1- yl) phenyl]

4- [4- (4-methylpiperazin-1-yl] phenylamino] quinolin-3-carbonitrile,

Yl) - [4- (4-methylpiperazin-1-yl) phenyl] amine,

(2,3-dimethylquinolin-4-yl) - [4- (4-methylpiperazin-1-yl) phenyl]

(4-methylpiperazin-1-yl) phenyl] - (1, 2,3,4,5,6,7,8-octahydroacridin-9-yl)

(3-ethyl-2-methylquinolin-4-yl) -methyl- [4- (4-methylpyrrolazin-1-yl) phenyl] amine.

Another possible subgroup of compounds of formula II are compounds of formula IIC, their pharmaceutically acceptable salts or esters.

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₁₀ , R ₁₁ , m, and t are as described in Formula II; i is 1 or 2; j is 0 to 3;

Another possible sub-group of compounds of formula II is a compound of formula IID, a pharmaceutically acceptable salt or ester thereof.

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , m, and t are as described in Formula II; p is 1 to 3; For example,

Wherein m is 1 and R &lt; 3 &gt; is (C1-C6) alkoxy; or

The following compounds.

2- [4- (4-acridin-9-yl) aminophenyl] piperazin-1-ylphenyl] ethanol,

(4-methoxyacetidin-9-yl) - [4- (4-methylpiperazin-1-yl) phenyl]

9-yl- [4- (4-methylpiperidin-1-yl) phenyl] amine,

Acridine-9-yl- [4- (3-hydroxymethylpiperidin-1-yl) phenyl] amine,

9-yl- [4-pyrrolidin-1-yl) phenyl] amine,

Yl] - [4- (4-cyclopropylpiperazin-1-yl) phenyl] amine,

9-yl- [4- (4-isopropylpiperazin-1-yl) phenyl] amine,

(Acridine-9-yl) -methyl- [4- (4-methylpiperazin-1-yl) phenyl]

9-yl- [2,5-diethoxy-4- (morpholin-4-yl) phenyl] amine.

In possible subgroups of compounds of formula II, IIA, IIB, IIC, or IID, Ra and Rb together with the N-atom to which they are attached form the following group.

Where R ₆ is (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkenyl, (C ₃ -C ₆₎ cycloalkyl or hydroxy (C ₁ -C ₆₎ alkyl, preferably R ₆ (C ₁ -C ₆ ) alkyl.

The compounds of formulas I and II and their subgroups IA, IB, IC, ID, IIA, IIB, IIC and IID and their pharmaceutically acceptable salts and esters are included within the scope of the present invention.

The compounds of the present invention have a chiral carbon atom in their structure. The present invention also encompasses all possible stereoisomers including the geometric isomers of the compounds of the present invention, such as Z and E isomers (cis and trans isomers) and optical isomers such as diastereomers and enantiomers Are included within the scope of the present invention. Moreover, the present invention includes all isomers, mixtures thereof, such as racemates. Each isomer may be obtained using the corresponding isomeric form of the starting material or may be separated after preparation of the desired compound using conventional separation methods. Conventional methods such as fractional crystallization and the like can be used to separate an optical isomer, for example, enantiomer, from the mixture.

Physiologically acceptable salts such as acid addition salts with organic and inorganic acids are well known in the pharmaceutical arts. Non-limiting examples of these salts include hydrochloride, bromate, sulfate, nitrate, phosphate, sulfonate, formate, tartrate, maleate, citrate, benzoate, salicylate and ascorbate. Pharmaceutically acceptable esters can be prepared by methods well known in the pharmaceutical arts and having pharmacological properties in free form. Non-limiting examples of these esters include aliphatic or aromatic alcohols, such as lower alkyl esters such as methyl, ethyl and propyl esters, and the like.

The terms used in this specification have the following meanings. Halogen or halorane means fluorine, chlorine, bromine or iodine. (C ₁ -C ₆ ) alkyl means a straight-chain or branched alkyl group having up to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, Butyl, I-butyl, t-butyl or s-butyl group. (C ₁ -C ₆₎ alkoxy (C ₁ -C ₆₎ alkyl is an -O- (C ₁ -C ₆₎ alkyl group as defined above. (C ₂ -C ₆ ) alkenyl means a straight or branched carbon chain having up to 6 carbon atoms, preferably 2 to 4, and having a double bond (s). (C ₂ -C ₆ ) alkynyl means a straight or branched carbon chain having up to 6 carbon atoms, preferably 2 to 4, and having a triple bond (s). Halo - (C ₁ -C ₆ ) alkyl means a (C ₁ -C ₆ ) alkyl group substituted by one or more halogens as defined above, such as, for example, trifluoromethyl, difluoromethyl and the like. Mono- or di- (C ₁ -C ₆ ) alkylcarbamoyl means a carbamoyl group that is N-substituted by one or two (C ₁ -C ₆ ) alkyl groups as defined above.

The compounds of the present invention may be prepared, for example, using the appropriate starting materials as described in B.F. Cain et al. in J. Med. Chem., Vol. 20 (8), 1977, pp. 987-996, and by W.A. Denny et al. in J. Med. Chem. Vol. 25, 1982, p. &Lt; / RTI &gt; 276-315, or in a similar manner. These references are incorporated herein by reference.

In general, the compounds of the present invention are prepared by the following scheme 1 or by a similar method.

Scheme 1:

In the above formula, Ra, Rb, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , m and t are as described above.

The reaction is a conventional acid-catalyzed coupling reaction of the chloro-compound of formula III with a substituted aromatic amine of formula IV. The reaction is carried out under acidic conditions in an appropriate solvent, such as an alcohol such as methanol, at room temperature or elevated temperature to obtain the compound of formula I ', which is then isolated from the reaction mixture in the usual manner.

The starting materials, compounds III and IV, are either commercially available or can be prepared as described above in B.F. Cain et al. in J. Med. Chem., Vol. 20 (8), 1977, pp. 987-996, and by W.A. Denny et al. in J. Med. Chem. Vol. 25, 1982, p. 276-315 or analogous methods.

Thus, the substituted aromatic NR ₁ -amine IV is prepared, for example, by reducing the corresponding sodium compound in the presence of a reducing agent such as SnCl ₂ .H ₂ O in a suitable solvent such as DMF. When R ₁ = (C ₁ -C ₆ ) alkyl is required, it is optionally alkylated with R ₁ by methods known in the literature.

Starting material III is prepared by Scheme 2 below.

Scheme 2:

In the above formula, Ra, Rb, R ₃ and m are as described above.

In Scheme 2, compound V is reacted with thionyl chloride under a small amount of DMF to give 9-chlorinated reactant III. The reaction is carried out at room temperature or at an elevated temperature.

It will be apparent to those of ordinary skill in the art that any starting materials or intermediates can be protected in such reactions, if necessary, by methods well known in the chemical art. Any protected functional group can be removed by methods known in the literature .

The synthetic routes described above illustrate the preparation of the compounds of the present invention and do not impose any limitation on the present invention. Other synthetic methods within the general knowledge of those skilled in the art are also within the scope of the present invention.

The compounds of the present invention can be converted, if necessary, into their pharmaceutically acceptable salts or esters using methods well known in the art.

The following examples are for the purpose of illustrating the present invention and do not limit the scope of the present invention.

Example 1

Yl [4- (4-methylpiperazin-1-yl) -phenyl] amine

Step 1

1.04 g (5.0 mmol) of N- (4-nitrophenyl) piperazine are dissolved in 5 ml of dimethylformamide. Sodium hydride (0.24 g, 6.0 mmol) was added in three portions under a stream of nitrogen to the reaction mixture and cooled for 10 min. After stirring for 301 minutes, 0.31 ml (6.0 mmol) of methyl iodine are added dropwise to the reaction mixture at 0 &lt; 0 &gt; C. After stirring at room temperature for 1 hour, the reaction mixture was evaporated to dryness and then subjected to silica gel column chromatography (methylene chloride: methanol: triethylamine = 94: 5: 1) to obtain 1.0 g (90% 4-nitrophenyl) piperazine is obtained.

Step 2

(45 mmol) of tin (II) chloride dihydrate and 20 ml of dimethylformamide were mixed and stirred at 80 占 폚 overnight . Most of the dimethylformamide is evaporated under vacuum. The remaining slurry is poured into ice water, neutralized with a sodium bicarbonate (saturated) solution and filtered. The filtrate is extracted several times with ethyl acetate and chloroform to obtain 0.636 g (74%) of 4- (4-methylpiperazin-1-yl) amine.

Step 3

0.488 g (2.5 mmol) of 9- (10H) acridone, 2.5 ml of thionyl chloride and a catalytic amount (number of times) of dimethylformamide are mixed at 80 deg. After stirring for 3 minutes, the reaction mixture is evaporated and the residue is dissolved in chloroform and poured into cold ammonia water. The ammonia solution is extracted several times with chloroform. The organic layers are combined, washed with 2M aqueous ammonia solution, dried over sodium sulphate and evaporated to give 0.517 g (97%) of 9-chloroacridine.

Step 4

0.191 g (1.0 mmol) of 4- (4-methylpiperazin-1-yl) aniline, 2.5 ml of methanol and concentrated hydrochloric acid are mixed and heated under reflux. 9-chloroacridine (1-1.5 equivalents) and 2.5 ml of methanol are separated and mixed and added in small portions to the reaction mixture. After stirring for 30 minutes, 2 drops of concentrated hydrochloric acid are added and stirred for 2 hours. The reaction mixture was then evaporated to dryness and chromatographed (silica gel column: 90% methylene chloride and 10% methanol in 100% methylene chloride; 4- (4-methylpiperazin-1-yl) aniline was eluted from the column , And the eluent was changed to methylene chloride: methanol: triethylamine = 94: 5: 1). 0.126 g (34%, chd tndbf 12%) of the title compound in pure state is obtained.

_{^{1 H NHR (DMSO-d 6}} , 500MHz): 8.05 (2H, m), 7.73 (2H, m), 7.66 (2H, m), 7.13 (2H, m), 6.97 (4H, m), 3.35 (4H MS (EI ⁺ ): 368 (M &lt; ⁺ & gt ^; ),

Example 2

9-yl- [2,5-diethoxy-4- (morpholin-4-yl) phenyl] amine

The title compound was prepared according to the procedure of step 4 of Example 1 substituting 2,5-diethoxy-4-morpholinoaniline dichloride for 4- (4-methylpiperazin-1-yl) 23%.

¹ H NHR (CDCl ₃ , 500 MHz): 8.19 (2H, m), 8.13 (2H, m), 7.56 (1H, s), 7.42 ), 3.91 (4H, m), 3.15 (4H, m), 3.10 (4H, q, J = 7.27Hz), 1.41 (6H, t, J = 7.27Hz); MS (ESI ⁺ TOF): 444 (M ^& lt ^{; +} & gt ^; ).

Example 3

Acridin-9-yl- [4- (morpholin-4-yl) phenyl] amine

The title compound is obtained in 64% overall yield by replacing 4- (4-methylpiperazin-1-yl) aniline with 4-morpholin-1-yl) aniline according to the procedure of step 4 of Example 1.

_{^{1 H NHR (CDCl 3, 500MHz}} ): 7.99 (4H, m), 7.55 (2H, m), 7.17 (2H, m), 7.17 (2H, m), 7.04 (2H, m), 6.88 (2H, m ), 3.88 (4 H, m), 3.15 (4 H, m); MS (ESI ⁺ TOF): 356 (M ^& lt ^{; +} & gt ^; ).

Example 4

(3-ethyl-2,8-dimethylquinolin-4-yl) - [4- (4-methylpiperazin-

The title compound is obtained in 27% overall yield by replacing 9-chloroacridine with 4-chloro-2,8-dimethyl-3-ethylquinoline according to the procedure of step 4 of Example 1.

_{^{1 H NHR (CDCl 3, 500MHz}} ): 7.60 (1H, m), 7.41 (1H, m), 7.16 (1H, m), 6.79 (2H, m), 6.62 (2H, m), 5.62 (1H, s ), 3.12 (4H, m), 2.79 (3H, s), 2.79 (2H, q, J = 7.63 Hz), 2.78 (3H, s), 2.59 (3H, t, J = 7.63 Hz); MS (ESI ⁺ TOF): 375 (M ^& lt ^{; +} & gt ^; ).

Example 5

(2-methylquinolin-4-yl) - [4- (4-methylpiperazin-1-yl) phenyl]

The title compound was obtained in 24% overall yield by replacing 9-chloroacridine with 4-chloro-2-methylquinoline according to the procedure of step 4 of Example 1.

_{^{1 H NHR (CDCl 3, 500MHz}} ): 8.02 (1H, m), 7.91 (1H, m), 7.64 (1H, m), 7.44 (1H, m), 7.23 (2H, m), 7.00 (2H, m ), 6.59 (1H, m), 3.26 (4H, m), 2.61 (4H, m), 2.55 (3H, s), 2.38 (3H, s); MS (ESI ⁺ TOF): 333 (M ^& lt ^{; +} & gt ^; ).

Example 6

[4- (4-methylpiperazin-1-yl) phenyl] - (quinolin-4-yl) amine

9-chloroacridine was replaced by 4-chloroquinoline according to the procedure of Step 4 of Example 1 to obtain the title compound in a total yield of 11%.

_{^{1 H NHR (CDCl 3, 500MHz}} ): 8.28 (1H, m), 8.25 (1H, m), 8.06 (1H, m), 7.66 (1H, m), 7.50 (1H, m), 6.97 (2H, m ), 3.25 (4H, m) , 2.64 (4H, m), 2.40 (3H, s), MS (ESI + TOF): 319 (M +)

Example 7

(3-ethyl-2,6-dimethylquinolin-4-yl) - [4- (4-methylpiperazin-

The title compound was obtained in 18% overall yield by replacing 9-chloroacridine with 4-chloro-1,6-dimethyl-3-ethylquinoline according to the procedure of step 4 of Example 1.

_{^{1 H NHR (CDCl 3, 500MHz}} ): 7.90 (1H, m), 7.49 (1H, m), 7.40 (1H, m), 6.81 (2H, m), 6.67 (2H, m), 3.12 (4H, m ), 2.77 (2H, q, J = 7.56 Hz), 2.78 (3H, s), 2.58 (4H, m) 7.56 Hz); MS (ESI ⁺ TOF): 375 (M ^& lt ^{; +} & gt ^; ).

Example 8

Methyl-quinolin-4-yl) - [4- (4-methylpiperazin-1-yl) phenyl] amine

The title compound is obtained in 5% overall yield by replacing 9-chloroacridine with 4-chloro-3-ethyl-6-methoxy-2-methylquinoline according to the procedure of step 4 of Example 1.

MS (ESI ⁺ TOF): 391 (M ^& lt ^{; +} & gt ^; ).

Example 9

(3-ethyl-2-methylquinolin-4-yl) - [4- (4-methylpiperazin- 1 -yl) phenyl]

Chloro-3-ethyl-2-methylquinoline with 9-chloroacridine according to the procedure of step 4 of Example 1 to give the title compound in 17% overall yield.

_{^{1 H NHR (CDCl 3, 500MHz}} ): 7.91 (1H, m), 7.72 (1H, m), 7.55 (1H, m), 7.25 (1H, m), 6.80 (2H, m), 6.67 (2H, m ), 5.72 (1H, s), 3.11 (4H, m), 2.79 (2H, q, J = 7.59Hz) (3H, t, J = 7.59 Hz); MS (ESI ⁺ TOF): 361 (M ^& lt ^{; +} & gt ^; ).

Example 10

(4-methoxyacridin-9-yl) - [4- (4-methylpiperazin-1-

According to the procedure of Step 3 of Example 1, 9-chloro-4-methoxyacridine was obtained by substituting 9-hydroxy-4-methoxyacridone for 9- (10H) -acridone, This was reacted with 4- (4-methylpiperazin-1-yl) aniline according to the procedure of step 4 of Example 1 to obtain the title compound in 24% overall yield.

MS (ESI ⁺ TOF): 399 (M ^& lt ^{; +} & gt ^; ).

Example 11

[4- (4-methylpiperazin-1-yl) phenyl] - (1,2,3,4-tetrahydroacridin-9-yl) amine

(10H) acridone was used instead of 9- (10H) -acridone instead of 1,2,3,4-tetrahydro-9- (10H) acridone in accordance with the process of Step 3 of Example 1 to obtain 9- , 2,3,4-tetrahydroacridine, which was reacted with 4- (4-methylpiperazin-1-yl) aniline according to the procedure of step 4 of Example 1 to give the title compound in 46% &Lt; / RTI &gt;

_{^{1 H NHR (CDCl 3, 500MHz}} ): 7.96 (1H, m), 7.72 (1H, m), 7.56 (1H, m), 7.27 (1H, m), 6.83 (2H, m), 6.73 (2H, m M), 1.84 (2H, m), 2.54 (2H, m), 5.82 (1H, s) ; MS (ESI ⁺ TOF): 373 (M ^& lt ^{; +} & gt ^; ).

Example 12

9-yl- [4- (piperidin-1-yl) phenyl] amine

0.202 g (1.0 mmol) of 1-bromo-4-nitrobenzene and 0.20 ml (2.0 mmol) of piperidine are dissolved in 3 ml of dimethylsulfoxide. To this was added 0.207 g (1.5 mmol) of potassium carbonate and the reaction mixture was heated to 100 &lt; 0 &gt; C. After 2 hours, 100 ml of water are added and the mixture is extracted several times with dichloromethane. The organic layers are combined, dried over sodium sulphate and evaporated to give crude 4- (piperidin-1-yl) -1-nitrobenzene. Piperidine-1-yl-1-nitrobenzene was used instead of 1-methyl-4- (4-nitrophenyl) piperazine according to the same procedures as step 2 of Example 2 to obtain 4- 1-yl aniline, which was reacted with 9-chloroacridine according to the procedure of Step 4 of Example 1 to give the title compound in a total yield of 6%.

_{^{1 H NHR (CDCl 3, 500MHz}} ): 8.05 (2H, m), 8.00 (2H, m), 7.48 (2H, m), 7.09 (4H, m), 6.86 (2H, m), 3.13 (4H, m ), 1.71 (4H, m), 1.58 (4H, m); MS (ESI ⁺ TOF): 354 (M ^& lt ^{; +} & gt ^; ).

Example 13

9-yl- [4- (4-methylpiperidin-1-yl) phenyl] amine

According to the procedure of Example 12, the title compound is obtained in 6% overall yield using 4-methylpiperidine instead of piperidine.

MS (ESI ⁺ TOF): 354 (M ^& lt ^{; +} & gt ^; ).

Example 14

Yl] [4- (3-hydroxymethylpyrrolidin-1-yl) phenyl] amine

According to the procedure of Example 12, the title compound is obtained in 3% overall yield using 3-hydroxymethylpiperidine instead of piperidine.

_{^{1 H NHR (CDCl 3, 500MHz}} ): 7.93 (2H, m), 7.81 (2H, m), 7.47 (2H, m), 7.04 (4H, m), 6.92 (2H, m), 3.68 (2H, m ), 3.59 (2H, m), 2.78 (1H, m), 2.61 (1H, m), 1.95 ); MS (ESI ⁺ TOF): 384 (M ^& lt ^{; +} & gt ^; ).

Example 15

Yl] [4- (pyrrolidin-1-yl) phenyl] amine

According to the procedure of Example 12, the title compound is obtained in 50% overall yield using pyrrolidine instead of piperidine.

_{^{1 H NHR (CDCl 3, 500MHz}} ): 8.00 (1H, m), 7.56 (2H, m), 7.18 (2H, m), 7.00 (2H, m), 6.50 (2H, m), 3.27 (4H, m ), 2.02 (4 H, m); MS (ESI ⁺ TOF): 340 (M ^& lt ^{; +} & gt ^; ).

Example 16

Acridin-9-yl- [4- (piperazin-1-yl) phenyl] amine

(4-nitrophenyl) piperazine was used instead of 1- (4-nitrophenyl) piperazine according to the procedure described in step 2 of Example 1 to give 4- -Yl) aniline, which was reacted with 9-chloroacridine according to the procedure of step 4 of Example 1 to give the title compound in 16% overall yield.

_{^{1 H NHR (CD 3 OD,}} 500MHz): 8.21 (2H, m), 7.94 (4H, m), 7.42 (2H, m), 7.38 (2H, m), 7.20 (2H, m), 3.56 (4H, m), 3.43 (4H, m); MS (ESI ⁺ TOF): 355 (M ^& lt ^{; +} & gt ^; ).

Example 17

Acridine-9-yl- [4- (4-acetylpiperazin-1-yl) phenyl] amine

(Example 16) was dissolved in chloroform (2 ml), and thereto was added a solution of 7.1 mg (0.10 mmol) of acetyl chloride And a catalytic amount of pyridine and triethylamine. After stirring at room temperature for 2 hours, the solvent is removed under vacuum. The residue is subjected to silica gel chromatography (elution chloroform: methanol 6: 1). The fractions containing the title compound are combined and evaporated, then added to water and extracted with chloroform. After drying over sodium sulfate, the organic layer was evaporated to give the title compound (6%, 1% total yield).

MS (ESI ⁺ TOF): 397 (M ^& lt ^{; +} & gt ^; ).

Example 18

9-yl- [4- (4-benzylpiperazin-1-yl) phenyl] amine

Following the procedure of step 1 of Example 1, except substituting 9- [4- (piperazin-1-yl) phenyl) piperazine for N- (4-nitrophenyl) piperazine and benzyl bromide for methyl iodide (Yield 15%, overall yield 2%).

_{^{1 H NHR (CDCl 3, 500MHz}} ): 8.00 (4H, m), 7.48 (2H, m), 7.34 (4H, m), 7.28 (1H, m), 7.12 (4H, m), 6.88 (2H, m ), 3.59 (2H, s), 3.21 (4H, m), 2.63 (4H, m); MS (ESI ⁺ TOF): 445 (M ^& lt ^{; +} & gt ^; ).

Example 19

9-yl- [4- (4-isopropylpiperazin-1-yl) phenyl] amine

According to the procedure of Step 1 of Example 1, 9- [4- (piperazin-1-yl) phenyl] aminoacridine (Example 16) was used instead of N- (4-nitrophenyl) Using isopropyl iodine instead of iodine, the title compound is obtained (11%, overall yield 2%).

MS (ESI ⁺ TOF): 397 (M ^& lt ^{; +} & gt ^; ).

Example 20

2-4- [4- (1,2,3,4-tetrahydroacridin-9-yl) aminophenyl] piperazin-1-yl ethanol

0.14 ml (2.0 mmol) of 2-bromoethanol and 0.17 ml (2.4 mmol) of acetyl chloride are dissolved in 2 ml of dichloromethane. To this was added 0.28 ml (2.0 mmol) of triethylamine and the reaction mixture was stirred at room temperature. After 1 hour, 50 ml of dichloromethane are added to the reaction mixture, followed by a solution of sodium bicarbonate (saturated), and 10% aqueous citric acid and water. The organic layer is dried over sodium sulfate and evaporated to give 0.241 g (72%) dml 2-bromoethylacetate. According to the procedure of Step 1 of Example 1, 2- [4- (4-nitrophenyl) piperazin-1-yl] ethyl acetate (64%) was obtained using 2-bromoethyl acetate instead of methyl iodide . This is reduced according to the procedure of Step 2 of Example 1 to quantitatively obtain the corresponding amine 2- [4- (4-aminophenyl) piperazin-1-yl] ethyl acetate. 2- [4- (4-aminophenyl) piperazin-1-yl] ethyl acetate was reacted with 9-chloro-1,2,3,4-tetrahydroacridine in step 4 of Example 1 2-4- [4- (1,2,3,4-tetrahydroacridin-9-yl) aminophenyl] piperazin-1-yl ethyl acetate is obtained in 47% yield. This ester was treated overnight with 4 equivalents of lithium hydroxide in dioxane / water to yield the title compound in 60% yield (20% overall yield).

MS (ESI ⁺ TOF): 403 (M ^& lt ^{; +} & gt ^; ).

Example 21

2-4- [4- (acridin-9-yl) aminophenyl] piperazin-1-yl ethanol

According to the procedure of Step 1 of Example 1, 9- [4- (piperazin-1-yl) phenyl] aminoacridine (Example 16) was used instead of N- (4-nitrophenyl) 4- [4-amino- (1,2,3,4-tetrahydroacridin-9-yl) phenyl] piperazin-1-yl ethyl acetate was reacted with 2-bromoethyl- . This ester is treated with 8 equivalents of a solution of lithium hydroxide in dioxane / water overnight to yield the title compound in 37% yield (2% total yield).

MS (ESI ⁺ TOF): 399 (M ^& lt ^{; +} & gt ^; ).

Example 22

Acridine-9-yl- [4- (4-cyclopiperazin-1-yl) phenyl] amine

(16 mmol) of 9- [4- (piperazin-1-yl) phenyl] aminoacridine (Example 16) was dissolved in 1 ml of methanol, to which 57 μl (1.0 mmol) 1.1 mmol) of (1-ethoxycyclopropoxy) -trimethylsilane and a small amount of 3 A molecular weights. The reaction mixture is stirred at room temperature under a stream of nitrogen. After 30 minutes 28 mg (0.45 mmol) of sodium cyanoborohydride are added and the reaction mixture is heated at 50 &lt; 0 &gt; C overnight. The solvent was removed in vacuo and the residue was chromatographed (silica gel column, eluent chloroform / methanol 6: 1) to give 3.8 mg of the title compound (10%, overall yield 2%).

MS (ESI ⁺ TOF): 395 (M ^& lt ^{; +} & gt ^; ).

Example 23

4- [4- (4-methylpiperazin-1-yl) phenyl) amino] quinoline-3-carbonitrile

0.91 ml (10 mmol) of aniline and 1.69 g (10 mmol) of ethyl (ethoxymethylene) cyanoacetate are dissolved in 10 ml of pyridine and then heated under reflux. After 3 hours the pyridine is removed in vacuo and the residue is purified by chromatography (silica gel column, eluent 1% methanol in dichloromethane). 1.08 g (50%) of ethyl (anilinomethylene) cyanoacetate is obtained. The compound is cyclized by heating in a biphenyl / phenyl ether mixture. After cooling, the precipitate is filtered off and washed with diethyl ether to give 4-hydroxyquinoline-3-carbonitrile (49%). According to the procedure of Step 3 of Example 1, 4-chloro-3-cyanoquinoline (90%) is obtained using 4-hydroxyquinoline-3-carbonitrile instead of 9- (10H) acridone. This compound was reacted with 4- (4-methylpiperazin-1-yl) aniline according to the procedure of step 4 of Example 1 to give the title compound in 12% yield (overall yield 3%).

¹ H NHR (CDCl ₃ , 500 MHz): 8.66 (1H, s), 8.01 (1H, m), 7.78 (1H, m), 7.73 ), 6.94 (2H, m), 3.29 (4H, m), 2.63 (4H, m), 2.39 (3H, s); MS (ESI ⁺ TOF): 344 (M ^& lt ^{; +} & gt ^; ).

Example 24

(3-isopropyl-2-methylquinolin-4-yl) - [4- (4-methylpiperazin-

4.56 ml (50 mmol) of aniline and 10.7 ml (60 mmol) of ethyl 2-isopropylacetoacetate are mixed with 50 ml of chloroform, to which 0.48 g (2.5 mmol) of p-toluenesulfonic acid is added. The reaction mixture is refluxed while continuously removing water produced during the reaction. After 2 days, the chloroform was removed under vacuum, and the residue was refluxed in 10 ml of phenyl ether. After cooling, the precipitate is filtered and washed with diethyl ether to give 4-hydroxy-3-isopropyl-2-methylquinoline (21%). 4-hydroxy-3-isopropyl-2-methylquinoline (100%) is obtained instead of 9- (10H) acridone according to the process of Step 3 of Example 1. This was reacted with 4- (4-methylpiperazin-1-yl) aniline according to the procedure of step 4 of Example 1 to give the title compound in 61% yield (overall yield 13%).

_{^{1 H NHR (CDCl 3, 500MHz}} ): 7.95 (4H, m), 7.73 (1H, m), 7.54 (1H, m), 7.24 (1H, m), 6.79 (2H, m), 6.60 (2H, m ), 5.72 (1H, s), 3.61 (1H, q, J = 7.28), 3.11 (4H, m), 2.81 (3H, s), 2.57 6H, d, J = 7.28); MS (ESI ⁺ TOF): 375 (M ^& lt ^{; +} & gt ^; ).

Example 25

(2,3-dimethylquinolin-4-yl) - [4- (4-methylpiperazin-1-yl) phenyl]

According to the procedure of Example 24, 2-methylacetoacetate was used instead of ethyl 2-isopropylacetoacetate to give the title compound in a yield of 11%.

_{^{1 H NHR (CDCl 3, 500MHz}} ): 8.02 (1H, m), 7.78 (1H, m), 7.59 (1H, m), 7.33 (1H, m), 6.83 (2H, m), 6.69 (2H, m ), 5.90 (1H, s), 3.13 (4H, m), 2.73 (3H, s), 2.58 (4H, m), 2.35 (3H, s), 2.24 MS (ESI ⁺ TOF): 347 (M ^& lt ^{; +} & gt ^; ).

Example 26

Phenyl] - (2-methyl-1,2,3,4-tetrahydroacridin-9-yl) amine

2.37 g (10 mmol) of 2-aminobenzoic acid and 1.23 ml (10 mmol) of 4-methylcyclohexanone are dissolved in 10 ml of phosphorus oxychloride and the reaction mixture is heated under reflux in a stream of nitrogen. After 3 hours, most of the phosphorous oxychloride is removed under vacuum. The residual brown syrup is poured into an aqueous solution of cold sodium bicarbonate (saturated) and washed once with chloroform. The yellow precipitate formed in the basic solution is filtered to give 2-methyl-1,2,3,4-tetrahydro-9- (10H) -acridone (46%). Methyl-1,2,3,4-tetrahydro-9- (10H) -acridone was used instead of 9- (10H) -acridone in accordance with the process of Step 3 of Example 1 To give 9-chloro-2-methyl-1,2,3,4-tetrahydroacridine (40%). This was reacted with 4- (4-methylpiperazin-1-yl) aniline according to the procedure of step 4 of Example 1 to obtain the title compound in 395 yield (overall yield 7%).

_{^{1 H NHR (CDCl 3, 500MHz}} ): 7.97 (1H, m), 7.70 (1H, m), 7.55 (1H, m), 7.24 (1H, m), 6.83 (2H, m), 6.72 (2H, m ), 5.81 (1H, br s), 3.23 (1H, m), 3.14 (5H, m), 2.86 (1H, m), 2.57 ), 2.03 (1H, m), 1.93 (1H, m), 1.57 (1H, m), 1.10 (3H, d); MS (ESI ⁺ TOF): 387 (M ^& lt ^{; +} & gt ^; ).

Example 27

Yl) phenyl] - (7,8,9,10-tetrahydro-6H-cyclohepta [b] quinolin-11-yl) amine

The title compound (0.2%) is obtained according to the procedure of Example 26, substituting cycloheptanone for 4-methylcyclohexanone.

(ESI ⁺ TOF): 387 (M ^& lt ^{; +} & gt ^; ).

Example 28

Phenyl] - (2,7-dimethyl-1,2,3,4-tetrahydroacridin-9-yl) amine

According to the procedure of Example 26, 2-amino-5-methylbenzoic acid was used instead of 2-aminobenzoic acid to give the title compound (4%).

¹ H NHR (CDCl ₃ , 500 MHz): 8.10 (1H, m), 7.43 (2H, m), 6.85 (1H, m), 3.18 (4H, m), 2.78 (1H, m), 2.61 (4H, m), 2.37 (3H, s), 2.33 ), 1.91 (1H, m), 1.52 (1H, m), 1.09 (1H, m), 1.10 (3H, d); MS (ESI ⁺ TOF): 401 (M ^& lt ^{; +} & gt ^; ).

Example 29

(8-fluoro-l, 2,3,4-tetrahydroacridin-9-yl) - [4- (4-methylpiperazin-

According to the procedure of Example 26, 2-amino-6-fluorobenzoic acid was used instead of 2-aminobenzoic acid to give the title compound (3%).

_{^{1 H NHR (CDCl 3, 500MHz}} ): 7.89 (1H, m), 7.51 (1H, m), 7.05 (1H, m), 6.87 (2H, m), 6.82 (2H, m), 3.22 (4H, m ), 3.14 (2H, m), 2.66 (4H, m), 2.41 (3H, s), 2.34 (2H, m), 1.88 (2H, m), 1.67 (2H, m); MS (ESI ⁺ TOF): 391 (M ^& lt ^{; +} & gt ^; ).

Example 30

Phenyl] - (1,1,3,3-tetramethyl-1,2,3,4-tetrahydroacridin-9-yl) amine

1.49 ml (10 mmol) of ethyl 2-aminobenzoate and 1.73 ml (10 mmol) of 3,3,5,5-tetramethyl-cyclohexanone are mixed with 20 ml of toluene. 20 ml (0.1 mmol) of p-toluenesulfonic acid is added thereto. The reaction mixture is refluxed while continuously removing water produced during the reaction. After 9 hours, the toluene was removed under vacuum and the residue was refluxed in 10 ml of phenyl ether. After cooling, the precipitate is filtered off and washed with diethyl ether to give 1,1,3,3-tetramethyl-1,2,3,4-tetrahydro-9 (10H) -acridone (18%). According to the procedure of Step 3 of Example 1, 1,1,3,3-tetramethyl-1,2,3,4-tetrahydro-9 (10H) -aspartin was used instead of 9- (10H) 9-chloro-1,1,3,3-tetramethyl-1,2,3,4-tetrahydro-9 (10H) -acridine (21%) is obtained. This product was reacted with 4- (4-methylpiperazin-1-yl) aniline according to the procedure of Step 4 of Example 1 to obtain the title compound (yield: 3%, overall yield: 0.1%).

MS (ESI ⁺ TOF): 429 (M ^& lt ^{; +} & gt ^; ).

Example 31

(1,4-methano-1,2,3,4-tetrahydroacridin-9-yl) - [4- (4-methylpiperazin-

The title compound is obtained according to the procedure of Example 30, substituting norcamphor in place of 3,3,5,5-tetramethyl-cyclohexanone. (Overall yield 1%).

_{^{1 H NHR (CDCl 3, 500MHz}} ): 7.99 (1H, m), 7.84 (1H, m), 7.58 (1H, m), 7.38 (1H, m), 7.02 (2H, m), 6.91 (2H, m ), 6.13 (1H, s), 3.44 (1H, m), 3.21 (4H, m), 3.00 MS (ESI ⁺ TOF): 385 (M ⁺ ), 1.77 (2H,

Example 32

Phenyl] - (1,2,3,4,5,6,7,8-octahydroacridin-9-yl) amine

According to the procedure of Example 30, 2-amino-1-cyclohexene-1-carboxylate was used in place of ethyl 2-aminobenzoate and cyclohexanone was used in place of 3,3,5,5-tetramethyl- &Lt; / RTI &gt; to give the title compound. (Overall yield 0.2%).

MS (ESI ⁺ TOF): 377 (M ^& lt ^{; +} & gt ^; ).

Example 33

(3-ethyl-2-methylquinolin-4-yl) -methyl- [4- (4-methylpiperazin- 1 -yl) phenyl]

(3-ethyl-2-methylquinolin-4-yl) - [4- (4-methylpiperazin- 1 -yl) -piperazine was obtained in accordance with the process of Step 1 of Example 1 instead of N- ) Phenyl] amine (example 9), the title compound is obtained (overall yield 12%).

_{^{1 H NHR (CDCl 3, 500MHz}} ): 8.03 (1H, m), 7.58 (2H, m), 7.34 (1H, m), 6.81 (2H, m), 6.42 (2H, m), 3.33 (3H, s ), 3.07 (4H, m), 2.80 (3H, s), 2.71 (2H, q, J = 7.50Hz), 2.57 7.50Hz); MS (ESI ⁺ TOF): 375 (M ^& lt ^{; +} & gt ^; ).

Example 34

(Acridine-9-yl) -methyl- [4- (4-methylpiperazin-1-yl) phenyl] amine

9-yl [4- (4-methylpiperazin-1-yl) -phenyl] amine (prepared according to the procedure of Step 1 of Example 1) was used instead of N- (4-nitrophenyl) Example 1) was substituted for the title compound (overall yield 9%).

_{^{1 H NHR (CD 3 OD,}} 500MHz): 7.8 (2H, br s), 7.54 (2H, m), 7.48 (2H, m), 6.98 (4H, m), 6.79 (2H, m), 3.77 (3H , s), 3.18 (4H, m), 2.6 (4H, m), 2.36 (3H, s); MS (ESI ⁺ TOF): 383 (M ^& lt ^{; +} & gt ^; ).

The compounds of the present invention exhibit an interesting pharmacological activity, i.e. an antagonistic affinity to alpha-2 adrenoceptors. This activity is shown by the following pharmacological experiments.

Experimental Example I: Binding Affinity

Three kinds of human alpha-2 Adreno receptor subtype of the test compound of the present invention affinity binding Kyung analysis with ³ H- Lau monthly letter (3H-rauwolscine) for the (alpha -2A, -2B alpha, alpha -2C) . It consists of a physiological material composed of membranes from Shionogi S115 cells stably transfected with one of three human alpha-2 subtypes (A. Marjamaeki et al., Biochem. Biophys. A total of 90 μl of a membrane suspension (about 10 μg total protein per sample) and 1 nM ³ H-laurethase (specific activity 75-85 Ci / mmol) (50 mM KH ₂ PO ₄ , pH 7.5, room temperature). Non-specific binding is defined by 100 μM oxymetazoline and corresponds to 4-10% of total binding. After 30 minutes at room temperature, incubation is stopped (TomTec 96 harvester) with pre-immersed GF / B glass fiber mat (Wallac Oy) and washed with ice cold 50 mM KH ₂ PO ₄ (pH 7.5, room temperature). After drying, (Meltilex, Wallac Oy) was dissolved in a filter mat (WallacOy) and the binding activity was measured (BetaPlate; Wallac Oy). The IC ₅₀ 's is calculated according to Cheng Prussoff's equation (Ki = IC ₅₀ / (1+ [ ³ H-ligand] / K _{d, 3H-ligand} )).

The Ki values of Compound 1 obtained in three independent experiments are as follows;

Alpha-2A adrenoceptor: 3150 + - 50 nM

Alpha-2B adrenoceptor: 1470 + - 130 nM

Alpha-2C adrenoceptor: 28 +/- 2 nM

Experimental Example II: Antagonism

Antagonism is mediated by the action of epinephrine (G) on the G protein in membranes of CHO cells transformed with one of the three human alpha-2 subtypes (K. Pohjanoksa et al., Eur. J. Pharmacol., 335, - stimulating ³⁵ S-GTP? S binding (RR Jasper et al., Biochem. Pharmacol., 55, 1998, p 1035). Samples with 12 concentrations of membranes (5-10 microns protein per sample) and experimental compound were incubated at room temperature with a defined concentration of epinephrine (5 μM for alpha-2A, 15 μM for alpha-2B, 5 μM for alpha-2C ) Were preincubated for 30 minutes in 50 mM Tris, 5 mM MgCl ₂ , 150 mM NaCl, 1 mM DTT, 1 mM EDTA, 10 μM GDP, 30 μM ascorbic acid, pH 7.4. Then, a trace amount of ³⁵ S-GTP? S (0.08 nM-0.15 nM, specific activity 1250 Ci / mmol) is added to the culture mixture. After further incubation at room temperature for 30 minutes, the culture is stopped by rapid vacuum filtration through a glass fiber filter. The filter is washed three times with 5 ml of ice-cold wash buffer (20 mM Tris, 5 mM MgCl ₂ , 1 mM EDTA, pH 7.4 at room temperature), then dried and counted at the scintillation counter. The experiment is repeated at least three times. The K _b value of the compound 1 was confirmed to be as follows.

Alpha -2A adrenoceptor: 1495 ± 270 nM

Alpha-2B adrenoceptor: 2175 + 345 nM

Alpha-2C adrenoceptor: 16 6 nM

Experimental Example III: Antagonism of the X-medetomidine-induced kinetic inhibition by atipamozole other than Compound 1; Experiment of alpha-2C selectivity of Compound 1 in vivo

Dexmedetomidine and atipamozole are both very potent and specific alpha-2 adrenoreceptive agonists and antagonists, respectively, which lack alpha-2 subtype selectivity (H. Scheinin et al., European Journal of Pharmacology , Molecular Section, vol. 151 (1), 1988, pp. 35-42). Alpha-2 agonist-induced sedation is known as an alpha-2A agonist-induced sedative that can be antagonized by alpha-2A antagonists (J. Sallinin et al., Mol. Pharmacol. 36-46, and A. Haapalinna et al., Naunyn-Schimiedeberg ' s Arch Pharmacol. Vol. 356, 1997, p. The sedative effect of alpha-2 agonists in mice is measured by inhibition of motor activity. Therefore, we compared the ability of Compound 1 and atipamycin to antagonize dexmedetomidine-induced kinetic inhibition of these compounds in vivo to assess alpha-2A adrenoreceptor antagonism (and alpha-2C selectivity) Respectively.

Spontaneous locomotor activity of a total of 76 male NMRI mice (B & K, Sweden) was measured by placing each animal in a polypropylene animal cage (38 x 22 x 15 cm). The animal cage is surrounded by an infrared beam designed for activity measurement (Photobeam Activit System PAS, Cage Rack, Sa Diego Instruments, San Diego, Calif., USA). Animals are injected with multiple doses of compound or atipamozole 20 minutes before the injection of dexmedetomidine (50 nmol / kg s.c.). Spontaneous locomotor activity was measured 20 minutes after dexmedetomidine injection.

The results shown in Figure 1 show that atipamozole is 0.3 and 1.0 [mu] mol / kg s.c. (P < 0.01). &Lt; / RTI &gt; Compound 1 did not antagonize alpha-2-agonist-induced sedation in vivo, indicating lack of alpha-2A antagonism and alpha-2C selectivity.

Experimental Example IV: Stress-protective effect of Compound 1 in mouse forced swimming test

Exposure of experimental animals to strong stressful stimuli was observed to propagate behavioral conditions in despair. This is observed, for example, for forced swimming tests. Place the rat or mouse in a water-filled cylinder. After an exuberant attempt to flee, the animals take a floating floating attitude; Monitors range of subscales, which can be reduced by antidepressants or stress-protective agents. Transformed mice lacking functional alpha-2C adrenoreceptors tolerate swim-stress better than similarly treated natural-type controls (J. Sallinen et al., Mol. Psychiatry, vil.4 , 1999, pp. 443-452). Therefore, an increase in forced swimming activity can be used as a measure of alpha-2 C selective antagonism of a compound in vivo. Atipamozole, a non-selective antagonist, has no obvious stress-protective effect and does not exhibit increased vocalization in laboratory animals (T. Kauppila et al., Eur. J. Pharmacol., Vol. 205, p. 177-182). This results from the simultaneous alpha-2A antagonism of atipamozole. On the other hand, conventional non-specific alpha-2 adrenoceptors such as yohimbine are known to cause anxiety (S. Southwick et al., Arch. Gen. Psychiatry, vol. 54, 1997, p 749-758) .

The forced swimming test was carried out by the method described originally using stress-sensitive Balb / c mouse species (B & K, Sweden) (J. Crawley and L. Davis, Brain Research Bulletin, vol 8, 1982, p. 609-612, and US-A-5 902 807). Mice were dosed with vehicle (10 cm diameter, 18.5 cm height, 8 cm in height at 25 ° C with water at 25 ° C) with vehicle (injection of 0.1% DMSO, 5 mg / kg, subcutaneous injection), compound 10, 3 μmol / kg or atempermol 0.3 μmol / ), Respectively. The cumulative activity of each mouse was measured after 2 and 6 minutes after being placed in a container. Only mere escape attempts (scrambling) were recorded. The mice (96 total) were tested only once. The results are shown in Fig.

Compared with mice injected with vehicle, Compound 1 mice apparently tolerate the propagation in behavioral states in stress-induced despair (1-way, ANOVA, followed by LSD post hoc test; p = 0.013) Alpha-2C selective compound. Atipamozole had no obvious effect on activity relative to control mice (p = 0.52). A possible marginal effect of atipamozole is expected, however, since this subtype non-selective alpha-2 antagonist also blocks alpha-2C adrenoceptors. On the other hand, it is shown that a mouse administered with a dose of 0.3 mu mol / kg of atipamazole has an alpha-2A antagonistic action in vivo (Fig. 1). It has also been shown that the administered dose of atipamozole has a pronounced neurochemical effect, for example stimulating the noradrenaline secretion in the brain (Haapalinna et al., Naunyn-Schimiedeberg's Arch. Pharmacol. Vol. 356, 1997, p. 570-582). Therefore, the results show that alpha-2A adrenoreceptor antagonism of atipamozole counteracts stress-protective and antidepressant effects in vivo (J. Sallinen et al., Mol. Psychiatry, vol. 4, 1999, p. 443-452, and US-A-5 902 807).

In general, compounds of the present invention that exhibit alpha-2 adrenoreceptor antagonism are useful in the treatment of diseases or syndromes in which alpha-2 antagonists are effective. For example, the compounds may be used in the treatment of central nervous system disorders, such as central nervous system disorders, male erectile dysfunction, orthostatic hypotension, non-insulin dependent diabetes and obesity, for example. These compounds can also be used for adverse effects induced by alpha-2 acting drugs. Central nervous system diseases that can be treated with the compounds of the present invention are depression, anxiety, etc., post traumatic stress disorder, schizophrenia, Parkinson's disease, and other exercise disorders.

The selective alpha-2C antagonists of the present invention may be used in the treatment of various diseases or conditions of the central nervous system in which alpha-2C antagonists are indicated to be beneficial. (US-A-5 902 807gh, J. Sallinen et al. Neuroschence, vol. 86, 1998, p. 959-965, J. Sallinen et al., J. Neurosci., Vol.18, 1998, p. 3035-3042, and M. Bjorklund et al., Molucular Pharmacology, vol. 54, 1998, p. 569-76, the contents of which are hereby incorporated by reference). For example, in the treatment of schizophrenia and depression. Moreover, the selective alpha-2C antagonists of the present invention may be used as a stress-protective agent, or for the treatment of stress-induced central nervous system diseases, such as the post-traumatic stress disorder described in the above cited US Pat. No. 5,902,807 It can be used as a drug. Since alpha-2C antagonists stimulate central dopamine agonistic activity, they can be used as antiparkinsonian antipsychotic drugs for Parkinson's disease and other motor disorders. Moreover, since the alpha-2C antagonists of the present invention exhibit cognitive enhancing properties, these compounds can be used for the treatment of Alzheimer's disease or other dementia syndromes.

Due to the selectivity of tissue distribution, alpha-2C antagonists of the invention have little or no undesirable side effects such as cardiovascular effects.

The compounds of the present invention may be administered orally, topically, or parenterally.

The compounds of the present invention may be formulated with the active ingredient alone and / or with a pharmaceutically acceptable diluent, carrier and / or excipient, and may be formulated into various dosage forms, for example, Tablets, capsules, liquid preparations, emulsions, powders, and the like. Pharmaceutically acceptable diluents, carriers and / or excipients may be selected from those components which are routinely used in the field of pharmaceutical drugs by selecting the route of administration.

The amount of active ingredient in the dosage form may be varied, for example, from 0.01 to 75% by weight, depending on the type of dosage form, for example.

The specific dose level of the compounds of the present invention may be varied depending on various factors such as the compound to be administered, the sex, age, species, condition to be treated, route of administration and administration method, etc., of the patient to be treated. Thus, for adult men, the dosage for parenteral administration is typically 0.5 μg / kg to 10 mg / kg daily, and the oral dose is typically 5 μg / kg to 100 mg / kg per day.

The present invention provides a method of using a compound of the present invention for the treatment of a disease or syndrome, for example, a central nervous system disease or syndrome for which an alpha-2 antagonist, for example, an alpha-2C antagonist, . In such a method, a therapeutically effective amount of a compound of the invention is administered to a patient in need of such treatment. The present invention also provides uses for use in the manufacture of a medicament for use in the aforementioned indications of the compounds of the present invention.

Those of ordinary skill in the art will recognize that variations may be made therein without departing from the broad inventive concept thereof. Those of ordinary skill in the art will recognize that variations of these aspects are within the spirit and scope of the present invention,

As described above, it is an object of the present invention to provide antagonists of alpha-2 adrenoreceptors which can be used in the treatment of diseases and conditions of peripheral and central nervous system where alpha-2 antagonists are useful. Thus, the present invention provides compounds that are used as alpha-2 antagonists in the treatment of mammals, including humans and animals.

The present invention also provides compounds that are useful as selective alpha-2C antagonists in the treatment of various diseases and conditions of the central nervous system where alpha-2C antagonists are useful.

Claims (31)

Wherein the antagonist of an alpha-2 adrenoreceptor of a compound of formula I, a pharmaceutically acceptable salt or ester thereof, is used in the manufacture of a medicament for the treatment of a disease or syndrome useful for the treatment. From here, R ₁ is H or (C ₁ -C ₆ ) alkyl; Each R ₂ is independently OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₁ -C ₆₎ alkoxy, halo (C ₁ -C ₆₎ alkyl, NO ₂ , NH _2, mono- or di - (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl, -S- or hydroxy (C ₁ -C ₆₎ alkyl; A is a benzene ring or (C ₅ -C ₇₎ cycloalkyl; When A is benzene sun dog, each R ₃ is independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₁ -C ₆₎ alkoxy, halo - (C ₁ - C ₆₎ alkyl, NO _2, NH _2, mono- or di - (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl, -CO, mono- or di - (C ₁ -C ₆₎ - alkyl carbamoyl, (C ₁ -C ₆₎ alkyl, -S-, hydroxy (C ₁ -C ₆₎ alkyl, or NH ₂ -CO-; When A is (C ₅ -C ₇₎ cycloalkyl, each R ₃ is independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, mono-or di - (C ₁ -C ₆₎ alkylamino, or hydroxy (C ₁ -C ₆₎ alkyl; R ₄ and R ₅ have the following structure together with the N-atom to which they are bonded. Wherein X is O or N = R &lt; _{6 &} gt ;. R ₆ is selected from the group consisting of H, NH ₂ , (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, CN- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy- C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkyl, -CO-, -CO- NH _2, mono- or di - (C ₁ -C ₆₎ alkyl, carbamoyl, hydroxy (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆₎ cycloalkyl, phenyl, naphthyl and naphthyl or benzyl, where the above-mentioned phenyl, naphthyl, or benzyl are independently OH, _{halogen, NO 2, NH 2, (} C 1 - C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, mono-or di - (C ₁ -C ₆₎ alkylamino, halo or - (C ₁ -C ₆₎ optionally substituted with 1 to 3 substituents selected from alkyl . Or R &lt; ₄ &gt; and R &lt; ₅ &gt; together with the N-atom to which they are attached form the following structure. Wherein n is 1 or 2; R ₆ is as defined above; r is 0 to 3; Or R ₄ and R ₅ together with the N atom to which they are attached form a 1-imidazolyl, 1-imidazolinyl, or 1-triazolyl, which are each independently (C ₁ -C ₆ ) alkyl or the substituents R ₇ NH ₂ in which 1 to 3 may be optionally substituted; Or one of R ₄ and R ₅ is SO ₂ R ₈ and the remainder of R ₄ and R ₅ is H or (C ₁ -C ₆ ) alkyl; R ₈ is (C ₁ -C ₆₎ alkyl, phenyl, naphthyl and naphthyl or benzyl, where the above-mentioned phenyl, naphthyl, or benzyl are independently OH, _{halogen, NO 2, NH 2, (} C 1 -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, or mono- or di - (C ₁ -C ₆₎ may be optionally substituted with 1 to 3 R ₉ substituents selected from alkylamino; And Ra and Rb are independently H, OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₂ -C ₆₎ alkynyl, (C ₁ -C ₆₎ alkoxy a (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl, -S-, or CN, halo (C ₁ -C ₆₎ alkyl, NO _2, NH _2, mono- or di; Or R <a> and R <b> together with the carbon to which they are attached form a fused benzene ring. Independently ring is condensed benzene OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₁ -C ₆₎ alkoxy, halo - (C ₁ -C ₆₎ alkyl, NO _2, NH _2, mono- or di - (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl, -CO-, mono- or di - (C ₁ -C ₆₎ - alkyl carbamoyl, ( C ₁ -C ₆₎ alkyl, -S-, hydroxy (C ₁ -C ₆₎ alkyl, or is a NH ₂ -CO- the substituents R'3 optionally may be substituted from 1 to 3; Or Ra and Rb may be condensed with a 5- to 7-membered carbocyclic ring together with the carbon to which they are attached. Are each independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, mono-or di - (C ₁ -C ₆₎ alkyl amino, halo (C ₁ -C ₆₎ alkyl Gt; R &lt; _{10 &} gt ;, wherein R &lt; ₁₀ &gt; Or Ra and Rb may form bicyclo [2,2,1] -heptane fused with the carbon ring atoms to which they are attached, which are independently OH, halogen, (C ₁ -C ₆ ) alkyl, or C ₁ -C ₆ ) alkoxy; Or Ra and Rb may form a ring heteroatom = NR a 5-or 6-membered heterocyclic ring condensed with ₁₁ with the carbon ring atoms to which they are bonded, they are optionally 1 to 3 chihoen with R ₁₀ defined before Can be; R ₁₁ is H or (C ₁ -C ₆ ) alkyl or is each independently selected from the group consisting of OH, halogen, NO ₂ , NH ₂ , (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, di - (C ₁ -C ₆₎ may be arbitrarily substituted with 1 to 3 alkyl amino substituents R _11;. m is 0 to 3; ego, t is from 0 to 3; 7. The use of a compound of formula I according to claim 1, wherein the compound of formula I is a pharmaceutically acceptable salt or ester thereof. Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₁₀ , m and t are as defined in claim 1; I is 1 to 3; j is 0 to 4; 11. The use of a compound of formula I according to claim 1, wherein the compound of formula I is a pharmaceutically acceptable salt or ester thereof. Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , m and t are as defined in claim 1; Ra and Rb are as H, OH, halogen, (C ₁ -C ₆₎ independently alkyl, (C ₂ -C ₆₎ alkenyl, (C ₂ -C ₆₎ alkynyl (C ₁ -C ₆₎ alkoxy, halo - (C ₁ -C ₆ ) alkyl, NO ₂ , NH ₂ , mono- or di- (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₆ ) alkyl-S- or CN; Alternatively, Ra and Rb may form a 5- to 7-membered ring fused together with the carbon ring atoms to which they are attached. The ring may be optionally substituted with 1 to 3 substituents R &lt; ₁₀ &gt;. R ₁₀ is independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, mono-or di - (C ₁ -C ₆₎ alkylamino or hydroxy (C ₁ -C ₆ ) Alkyl. 3. The use of a compound of formula I according to claim 1, wherein the compound of formula I is a pharmaceutically acceptable salt or ester thereof. Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₁₀ , R ₁₁ , m and t are as defined in claim 1; i is 1 or 2; j is 0-3. 3. The use of a compound of formula I according to claim 1, wherein the compound of formula I is a pharmaceutically acceptable salt or ester thereof. Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , m and t are as defined in claim 1; p is from 0 to 3; In claim 5, m is 1 and R ₃ is (C ₁ -C ₆₎ alkoxy I, its pharmaceutically salts or esters Use of acceptable. Use of compound I, a pharmaceutically acceptable salt or ester thereof, according to any one of claims 1 to 6, wherein R &lt; ₄ &gt; and R &lt; ₅ &gt; have the following structure together with the N- atom to which they are attached. Wherein X is as defined in claim 1. Use of a compound according to any of claims 1 to 7, wherein X is = NR &lt; _{6 &} gt ;, a pharmaceutically acceptable salt or ester thereof. According to claim any claim 1 to 8 wherein, R ₆ is (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₃ -C ₆₎ cycloalkyl, or hydroxy (C ₁ -C ₆ ) alkyl, a pharmaceutically acceptable salt or ester thereof. 10. The method of claim 9, wherein, R ₆ is (C ₁ -C ₆₎ alkyl, compounds of formula I, its pharmaceutically salts or esters Use of acceptable. Use of a compound according to any one of claims 1 to 10 for the preparation of a medicament for use as a selective alpha-2C antagonist, a pharmaceutically acceptable salt or ester thereof. Use of a compound of formula I, or a pharmaceutically acceptable salt or ester thereof, for the manufacture of a medicament for the treatment of various diseases of the central nervous system, according to any one of claims 1 to 11. A compound of formula II, a pharmaceutically acceptable salt or ester thereof. In this formula, R ₁ is H or (C ₁ -C ₆ ) alkyl; Each R ₂ is independently OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₁ -C ₆₎ alkoxy, halo - (C ₁ -C ₆₎ alkyl, NO _2, NH _2, mono- or di - (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl, -S-, or hydroxy (C ₁ -C ₆₎ alkyl; A is a benzene ring or (C ₅ -C ₇₎ cycloalkyl; When A is a benzene ring, each R ₃ is independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₁ -C ₆₎ alkoxy, halo - (C ₁ - C ₆₎ alkyl, NO _2, NH _2, mono- or di - (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl, -CO-, mono- or di - (C ₁ -C ₆₎ alkyl carbamoyl, (C ₁ -C ₆₎ alkyl, -S-, hydroxy is hydroxy (C ₁ -C ₆₎ alkyl, NH ₂ -CO-.; When A is a (C ₅ -C ₇₎ cycloalkyl, each R ₃ is independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, mono-or di - (C ₁ -C ₆₎ alkyl amino or hydroxy (C ₁ -C ₆₎ alkyl; R &lt; ₄ &gt; and R &lt; ₅ &gt; together with the N-atom to which they are attached form a group of the formula: Wherein X is O or = NR &lt; _{6 &} gt ;; R ₆ is H, OH, NH ₂ , (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, CN- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) - (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkyl, -CO-, -CO- NH _2, mono- or di - (C ₁ -C ₆₎ alkyl, carbamoyl, hydroxy (C ₁ - C ₆₎ alkyl, (C ₃ -C ₆₎ cycloalkyl, or benzyl, the above-mentioned benzyl here are each independently OH, _{halogen, NO 2, NH 2, (} C 1 -C 6) alkyl, (C ₁ -C ₆₎ alkoxy, mono- or di-optionally substituted with a substituent of (C ₁ -C _{6) 1} to 3 selected from alkyl, - (C ₁ -C ₆₎ alkyl, or halo; Or R &lt; ₄ &gt; and R &lt; ₅ &gt; together with the N-atom to which they are attached form the following group. Wherein n is 1 or 2; R ₆ is as defined above; r is 0 to 3; Or R ₄ and R ₅ together with the N atom to which they are attached form a 1-imidazolyl, 1-imidazolinyl, or 1-triazolyl. Each of which may be each independently (C ₁ -C _{6) 1} to 3 substituents selected from optionally alkyl or NH ₂ R ₇ optionally substituted; Ra and Rb is a H, OH, halogen, (C ₁ -C ₆₎ independently alkyl, (C ₂ -C ₆₎ alkenyl, (C ₂ -C ₆₎ alkynyl, (C ₁ -C ₆₎ alkoxy, (C ₁ -C ₆ ) alkyl, NO ₂ , NH ₂ , mono- or di- (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₆ ) alkyl-S- or CN; Or Ra and Rb together with the carbon to which they are attached form a condensed benzene ring. They are each independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₁ -C ₆₎ alkoxy, halo (C ₁ -C ₆₎ alkyl, NO _2, NH _2, mono- or di - (C ₁ -C ₆₎ alkyl is agate, (C ₁ -C ₆₎ alkyl, -CO-, mono- or di - (C ₁ -C ₆₎ alkyl carbamoyl, (C ₁ - C ₆₎ alkyl, -S- hydroxy - (C ₁ -C ₆₎ it may be substituted with alkyl or NH ₂ -CO- in which the substituents R'3 optionally 1 to 3. Or Ra and Rb may be condensed with a 5- to 7-membered carbocyclic ring together with the carbon to which they are attached. Are each independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, mono-or di - (C ₁ -C ₆₎ alkyl amino, halo (C ₁ -C ₆₎ alkyl , hydroxy (C ₁ -C ₆₎ alkyl may be substituted with substituents R ₁₀ optionally 1 to 3; Or Ra and Rb may form bicyclo [2,2,1] -heptane fused with the carbon ring atoms to which they are attached, which are independently OH, halogen, (C ₁ -C ₆ ) alkyl, or C ₁ -C ₆ ) alkoxy; Or Ra and Rb may form a ring heteroatom = NR a 5-or 6-membered heterocyclic ring condensed with ₁₁ with the carbon ring atoms to which they are bonded, they are optionally 1 to 3 chihoen with R ₁₀ defined before Can be; R ₁₁ is H or (C ₁ -C ₆ ) alkyl or is each independently selected from the group consisting of OH, halogen, NO ₂ , NH ₂ , (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, di - (C ₁ -C ₆₎ alkyl is an amino substituent R ₁₂ may be optionally substituted with 1 to 3; m is 0 to 3; And t is from 0 to 3; However, under the following conditions. a) when A is a benzene ring, m is 0 or 1, R ₁ is H, R ₃ is Cl or NO ₂ , Ra and Rb together with the carbon ring atom to which they are attached form a fused benzene ring, X is NR _6, R ₆ is _{H, -CH 3, -CH 2 CH} 3, not a -COCH _3, or -CO-NH _2.; b) when A is a benzene ring, Ra and Rb are not simultaneously H; c) when A is a benzene ring, m is 1, t is 0, R1 is H, Ra and Rb together with the carbon ring atom to which they are attached form a fused benzene ring, which ring may optionally be substituted with Br. X is O, R ₃ is not NO ₂ or -OCH _3. d) when A is a benzene ring, m is ㅐ, t is 0 and R ₁ is H and Ra and Rb are unsubstituted benzene rings condensed with the carbon to which they are attached, X is not O; e) the compound is 4- [4 - [(6-chloro-2-methyl-4-quinolinyl) amino] phenyl] Amino-4- [4 - [(3-chloro-4- (1 H-imidazol-1-ylmethoxy) Phenyl] amino] -7-methoxy-6-nitro-3-quinolinecarbonitrile. 14. The compound of formula &lt; RTI ID = 0.0 &gt; IIA, &lt; / RTI &gt; Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₁₀ , m and t are as defined in claim 1; i is from 1 to 3 and j is from 0 to 4. The method of claim 14, wherein i is 2, and j is 0 or 1, R ₁₀ is (C ₁ -C ₃₎ alkyl, and the pharmaceutically acceptable salts, or esters. 14. The compound according to claims 14 or 15, wherein m is 0 or 1; R ₃ is (C ₁ -C ₃ ) alkyl, a pharmaceutically acceptable salt thereof, or an ester thereof. A compound according to any one of claims 14 to 16, Phenyl] - (1, 2,3, 4-tetrahydroacridin-9-yl) amine, Yl] aminophenyl] pyrazin-1-yl ethanol, [4- (4-methylpyrrazin-1-yl) ) Phenyl] - (2-methyl-1,2,3,4-tetrahydroacridin-9-yl) amine, (8- fluoro-l, 2,3,4- tetrahydroacridine- Yl) phenyl] (2,3-dimethyl-1,2,4-triazol-1-yl) Yl) phenyl] - (7,8,9,10-tetrahydro-6H-cyclohepta [b] thiophene- Quinolin-11-yl) amine or [4- (4-methylpiperazin-1-yl) phenyl] - (1,1,3,3-tetramethyl-1,2,3,4-tetrahydroacry Pyridin-9-yl) amine, a pharmaceutically acceptable salt thereof, or an ester thereof. 14. A compound of formula IIB, or a pharmaceutically acceptable salt or ester thereof, according to claim 13. Wherein A, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , m and t are as defined in claim 1; Ra and Rb are independently H, OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₂ -C ₆₎ alkynyl, (C ₁ -C ₆₎ alkoxy, halo (C ₁ -C ₆₎ alkyl, NO _2, NH _2, mono- or di - (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl, or -S-, or CN; Or Ra and Rb together with the carbon ring atoms to which they are attached, form a 5- to 7-membered ring may form a click sayi carbonyl source, all of which are independently selected from OH, halogen, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, mono-or di - (C ₁ -C ₆₎ may be alkylamino, or hydroxy (C ₁ -C ₆₎ alkyl substituted with R _10, optionally substituted with 1 to 3. 19. A compound according to claim 18, wherein A is a benzene ring, a pharmaceutically acceptable salt or ester thereof. 19. A compound according to any one of claims 18 or 19, wherein m is 0 or 1, a pharmaceutically acceptable salt or ester thereof. A compound according to any one of claims 18 to 20, wherein R ₃ is (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkoxy, a pharmaceutically acceptable salt or ester thereof. 19. The method of claim 18 to claim 21, wherein one, and Ra and Rb are independently H or (C ₁ -C ₃₎ alkyl, where the (C ₁ -C ₃₎ alkyl is a straight or branched carbon chain of up to 3 carbon atoms Phosphorus compound, a pharmaceutically acceptable salt thereof, or an ester thereof. 19. The compound of claim 18, wherein A is a 6-membered carbocyclic ring and Ra and Rb form a 5-to 7-membered carbocyclic ring condensed with the carbon atom to which they are attached. Wherein the carbocyclic ring is optionally substituted with one to three substituents independently selected from OH, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or hydroxy (C ₁ -C ₆ ) A compound, a pharmaceutically acceptable salt, or an ester thereof. 23. Compounds according to any one of claims 18 to 23, wherein the compound is (3-ethyl-2,8-dimethylquinolin-4-yl- [4- (4-methylpiperazin- 1- yl) phenyl] (2-methylquinolin-4-yl) - [4- (4-methylpiperazin-1-yl) phenyl] (3-ethyl-2,6-dimethylquinolin-4-yl) - [4- (3-ethyl-6-methoxy-2-methylquinolin-4-yl) - [4- (3-ethyl-2-methylquinolin-4-yl) - [4- (4-methylpiperazin- 1- yl) phenyl] 4- [4- (4-methylpiperazin-1-yl] phenylamino] quinolin-3-carbonitrile, Yl) - [4- (4-methylpiperazin-1-yl) phenyl] amine, (2,3-dimethylquinolin-4-yl) - [4- (4-methylpiperazin-1-yl) phenyl] Phenyl] - (1, 2,3,4,5,6,7,8-octahydroacridin-9-yl) amine, or (3- (4-methylpiperazin- Ethyl-2-methylquinolin-4-yl) -methyl- [4- (4-methylpyrrolazin-1-yl) phenyl] amine; or a pharmaceutically acceptable salt or ester thereof. 14. The compound of formula I according to claim 13, its pharmaceutically acceptable salts or esters. Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₁₀ , R ₁₁ , m and t are as defined in claim 1; i is 1 or 2; j is 0 to 3; 14. The compound of claim 13, a pharmaceutically acceptable salt, or ester thereof. Wherein R ₁ , R ₂ , R ₃ , R ' ₃ , R ₄ , R ₅ , m and t are as defined in claim 1; p is from 0 to 3; 27. The method of claim 26 wherein, m is 1 and R ₃ is (C ₁ -C ₆₎ alkoxy, and the pharmaceutically acceptable salts, or esters. 26. The compound according to any one of claims 26-27, wherein the compound is 2- [4- (4-acridin-9-yl) aminophenyl] piperazin-1-ylphenyl] ethanol, (4-methoxyacetidin-9-yl) - [4- (4-methylpiperazin-1-yl) phenyl] 9-yl- [4- (4-methylpiperidin-1-yl) phenyl] amine, Acridine-9-yl- [4- (3-hydroxymethylpiperidin-1-yl) phenyl] amine, 9-yl- [4-pyrrolidin-1-yl) phenyl] amine, Yl] - [4- (4-cyclopropylpiperazin-1-yl) phenyl] amine, 9-yl- [4- (4-isopropylpiperazin-1-yl) phenyl] amine, (Acridine-9-yl) -methyl- [4- (4-methylpiperazin-1-yl) phenyl] Yl) - [2,5-diethoxy-4- (morpholin-4-yl) phenyl] amine A compound, a pharmaceutically acceptable salt thereof, or an ester thereof. A compound according to any one of claims 13 to 28, wherein Ra and Rb together with the N-atom to which they are attached form the following group, their pharmaceutically acceptable salts or esters. Where R ₆ is (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkenyl, (C ₃ -C ₆₎ cycloalkyl or hydroxy (C ₁ -C ₆₎ alkyl, preferably R ₆ (C ₁ -C ₆ ) alkyl. 30. The method of claim 29 wherein, R ₆ is (C ₁ -C ₆₎ alkyl, and the pharmaceutically acceptable salts, or esters. A pharmaceutical composition comprising as an active ingredient a compound of formula II of claim 13, a pharmaceutically acceptable salt or ester thereof, optionally together with a pharmaceutically acceptable diluent, carrier and / or excipient.