EP1263733A2 - Derivatives of quinoline as alpha-2 antagonists - Google Patents

Derivatives of quinoline as alpha-2 antagonists

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Publication number
EP1263733A2
EP1263733A2 EP01913918A EP01913918A EP1263733A2 EP 1263733 A2 EP1263733 A2 EP 1263733A2 EP 01913918 A EP01913918 A EP 01913918A EP 01913918 A EP01913918 A EP 01913918A EP 1263733 A2 EP1263733 A2 EP 1263733A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
phenyl
compound
alkoxy
mono
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01913918A
Other languages
German (de)
English (en)
French (fr)
Inventor
Siegfried Wurster
Mia Engström
Juha-Matti Savola
Iisa Höglund
Jukka Sallinen
Antti Haapalinna
Andrei Tauber
Anna-Marja Hoffr N
Harri Salo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Juvanita Pharma Ltd Oy
Original Assignee
Orion Oyj
Juvanita Pharma Ltd Oy
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Filing date
Publication date
Application filed by Orion Oyj, Juvanita Pharma Ltd Oy filed Critical Orion Oyj
Publication of EP1263733A2 publication Critical patent/EP1263733A2/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/16—Anti-Parkinson drugs
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/08—Nitrogen atoms
    • C07D219/10—Nitrogen atoms attached in position 9
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to therapeutically active derivatives of quinoline, including the pharmaceutically acceptable salts and esters thereof, and their use as alpha-2 antagonists.
  • Some compounds exhibiting alpha adrenergic activity are well known in the art. Those compounds may be used for the treatment of a wide variety of diseases and conditions of the peripheric system and the central nervous system (CNS).
  • CNS central nervous system
  • alpha adrenergic receptors are divided into alpha-1 and alpha-2 adrenoceptors, each of which are further divided into subtypes. Accordingly, alpha-2 adrenoceptors in humans have been subdivided into three pharmacological subtypes known as alpha-2A, alpha-2B and alpha-2C adrenoceptors. A fourth subtype, alpha-2D, is known in rat, bovine and porcine and it corresponds to alpha-2A in man. These subtypes have a distinct distribution in human and animal tissues. For instance, alpha-2C adrenoceptors are concentrated in the CNS and they appear to play a role in the modulation of various CNS-mediated behavioural and physiological responses.
  • atipamezole is a non-specific alpha-2 antagonists.
  • Atipamezole has been described in, for example, EP-A-183 492 (cf. p.13, compound XV) and A. 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 for the alpha-2C subtype and may be used in the treatment of mental illnesses, e.g.
  • WO-A-99 28300 discloses substituted imidazole derivatives having agonist-like activity for alpha-2B or 2B/2C adrenoceptors.
  • Medicinskaja parazitologija I parazitarnye bolezni vol.5, 1991 , 55-7
  • J. Med. Chem. vol.20(8), 1977, 987-996
  • An object of the present invention is to provide further antagonists of alpha-2 adrenoceptors that can be used for the treatment of diseases or conditions of the pheripheric or central nervous system where alpha-2 antagonists are indicated to be useful. Accordingly, an object of the present invention is to provide further compounds to be used as alpha-2 antagonist agents in the treatment of mammals, including humans and animals.
  • Another object of the present invention is to provide further compounds useful as selective alpha-2C antagonist agents for the treatment of various disorders or conditions of the central nervous system where alpha-2C antagonists are indicated to be useful.
  • Figure 1 shows the effects of atipamezole and compound 1 on dexmedetomidine-induced hypolocomotion.
  • Figure 2 shows the effects of atipamezole and compound 1 in a forced swimming test in Balb/c mice.
  • Rl is H or (C ⁇ -C-6)alkyl
  • each R2 is independently OH, halogen, (C- ⁇ -C6)alkyl, (C2-C6)alkenyl, (C-j-CsJalkoxy, halo(C ⁇ -C6)alkyl, NO2, NH2, mono- or di(C-
  • A is a benzene ring or (C5-C7)cycloalkyl
  • each R3 is independently OH, halogen, (C ⁇
  • each R3 is independently OH, halogen, (C-
  • R4 and R5 form, together with the N-atom to which they are attached,
  • R 6 is H, OH, NH2, (C ⁇ -C6)alkyl, (C2-
  • R4 and R5 form, together with the N-atom to which they are attached,
  • R4 and R5 form, together with the N-atom to which they are attached,
  • R4 and R5 is -SO2R8 and the other of R4 and R5 is H or (Ci- Cg)alkyl;
  • R ⁇ is (C-
  • Ra and Rb are independently H, OH, halogen, (C ⁇ -C5)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C ⁇ -C6)alkoxy, halo(C-
  • Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed benzene ring optionally substituted with one to three substituent(s) R'3 each independently being OH, halogen, (C- ⁇ -C6)alkyl, (C2-C6)alkenyl, (C-
  • Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed bicyclo[2.2.1]-heptane ring optionally substituted with one to four substituent(s) each independently being OH, halogen, (C-
  • R11 is H or (C ⁇ -C6)alkyl, or R-n is phenyl optionally substituted with one to three substituents R-12 each independently being OH, halogen, NO2, NH2, (C-j-C6)alkyl, (C-
  • the compounds of formula I can be used for the manufacture of a medicament for the treatment of diseases or conditions where alpha-2 antagonists are indicated to be effective.
  • A is a benzene ring
  • A is a (C5-C7)cycloalkyl
  • Ra and Rb are independently H, OH, halogen, (C-]-C6)alkyl, (C-2- C6)alkenyl, (C2-C6)alkynyl, (C-
  • C6)alkoxy or halo(C ⁇ -C-6)alkyl such as H, halogen, (C-i -C ⁇ Jalkyl or
  • (C ⁇ -C ⁇ )alkoxy e.g. H or (C-
  • Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed benzene ring unsubstituted or substituted with one to three, e.g one or two, such as one, substituent(s) R'3 each independently being OH, halogen, (C ⁇ -Cg)alkyl, (C2- C6)alkenyl, (C ⁇ -C6)alkoxy, halo-(C ⁇ -Cg)alkyl, NO2, NH2, mono- or di(C-
  • Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed five to seven membered carbocyclic ring optionally substituted with one to four, e.g. one or two, such as one, substituent(s) R-J Q each independently being OH, halogen, (C-
  • Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed bicyclo[2.2.1]-heptane ring optionally substituted with one to four, e.g. one or two, such as one, substituent(s) each independently being OH, halogen, (C ⁇ -C ⁇ )alkyl or (C-
  • R-l 1 is phenyl optionally substituted with one to three, e.g. one or two, such as one, substituents R12 each independently being OH, halogen, NO2, NH2, (C-
  • R4 and R5 form, together with the N-atom, 1-piperazinyl which is 4- substituted with R ⁇ , wherein R ⁇ is as defined above; e.g. (C-
  • R4 and R5 form, together with the N-atom, a morpholino ring
  • R4 and R5 form, together with the N-atom, a 1-piperidinyl or 1- pyrrolidinyl optionally substituted with R5, wherein R is as defined above, possibly (C-
  • R4 and Rs form, together with the N-atom, 1-imidazolyl, 1- imidazolinyl or 1-triazolyl, each of which can optionally be substituted with one to three, e.g. one or two, such as one, substituent(s) R7 each independently being (C-
  • R4 and R5 are -SO2R8 and the other of R4 and R5 is H or (C-
  • Re is independently (C-
  • m is 0 to 3; e.g. 0, 1 or 2; e.g. 0 or 1 ; such as 0;
  • t is 0 to 3; e.g. 0, 1 or 2; e.g. 0 or 1 ; such as 0; and/or
  • is H; (16) R-i is (C- ⁇ -C ⁇ )alkyl;
  • R2 is independently OH, halogen, (C ⁇ -C ⁇ )alkyl, (C2-C ⁇ )alkenyl, (C- ⁇ -C ⁇ )alkoxy, halo(C ⁇ -C ⁇ )alkyl, NO2, NH2, mono- or di(C ⁇
  • R3 is independently OH, halogen, (C-
  • a possible subgroup of the compound of formula I is a compound of formula IA:
  • , R2, R3, R4, R5, R10; m and t are as defined above; i is 1 to 3; and j is 0 to 4.
  • Another possible subgroup of the compound of formula I is a compound of formula IB:
  • Ra and Rb are independently H, OH, halogen, (C ⁇ -C ⁇ )alkyl, (C2- C ⁇ )alkenyl, (C2-C ⁇ )alkynyl, (C ⁇ -C ⁇ )alkoxy, halo(C ⁇ -C ⁇ )alkyl, NO2, NH2, mono- or di(C ⁇ -C ⁇ )alkylamino, (C- ⁇ -C ⁇ )alkyl-S- or CN; or Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed five to seven membered carbocyclic ring optionally substituted with one to three substituent(s) R-10 '. each independently being OH, halogen, (C-j-C ⁇ )alkyl, (C ⁇ -
  • Another possible subgroup of the compound of formula I is a compound of formula IC:
  • o> R 11 - m and t are as defined above; i is 1 or 2; and j is 0 to 3.
  • , R2, R3, R'3, R4, R5, m and t are as defined above and p is 0 to 3; for example wherein m is 1 and R3 is (C-j -C ⁇ )alkoxy.
  • R4 and R5 form, together with the N-atom to which they are attached,
  • Another embodiment of the invention provides new compounds of formula II:
  • R-l is H or (C-
  • each R2 is independently OH, halogen, (C-
  • A is a benzene ring or (C5-C7)cycloalkyl
  • each R3 is independently OH, halogen, (C-
  • each R3 is independently OH, halogen, (C-
  • R4 and R5 form, together with the N-atom to which they are attached,
  • R ⁇ is H, OH, NH2, (C ⁇
  • R4 and R5 form, together with the N-atom to which they are attached,
  • R4 and R5 form, together with the N-atom to which they are attached, 1- imidazolyl, 1-imidazolinyl or 1-triazolyl, each of which can optionally be substituted with one to three substituent(s) R7 each independently being (C-
  • Ra and Rb are independently H, OH, halogen, (C-
  • Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed benzene ring optionally substituted with one to three substituent(s) R'3 each independently being OH, halogen, (C ⁇ -C ⁇ )alkyl, (C2-
  • Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed five to seven membered carbocyclic ring optionally substituted with one to four substituent(s) R-
  • Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed bicyclo[2.2.1]-heptane ring optionally substituted with one to four substituent(s) each independently being OH, halogen, (C-
  • is H or (C-) -C ⁇ )alkyl, or R ⁇ 1 is phenyl optionally substituted with one to three substituents R-]2 each independently being OH, halogen, NO2, NH2, (C-
  • R-] , R2, R3, R4, R5, Rio- m ancl * are as defined in formula II; i is 1 to 3; and j is 0 to 4; for example
  • R-J O is (C ⁇ -C3)alkyl, wherein the (C-
  • C3)alkyl includes both straight and branched chain radicals of up to 3 carbon atoms
  • the compound is [4-(4-Methylpiperazin-1-yl)phenyl]-(1 , 2,3,4- tetrahydroacridin-9-yl)amine, 2- ⁇ 4-[4-(1 ,2,3,4-Tetrahydroacridin-9- yl)aminophenyl]piperazin-1 -yl ⁇ ethanol, [4-(4-Methylpiperazin-1 -yl)phenyl]-(2- methyl-1 ,2,3,4-tetrahydro-acridin-9-yl)amine, (8-Fluoro-1 ,2,3,4- tetrahydroacridin-9-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amine, [4-(4- Methylpiperazin-1 -yl)phenyl]-(2,7-dimethyl-1 ,2,3,4-tetrahydroacridin-9-yl)amine, [4-
  • Another possible subgroup of the compound of formula II is a compound of formula MB,
  • Ra and Rb are independently H, OH, halogen, (C ⁇ -C ⁇ )alkyl, (C2- C ⁇ )alkenyl, (C-2-C ⁇ )alkynyl, (C ⁇
  • A is a benzene ring
  • m is 0 or 1 ;
  • R3 is (C- ⁇ -C ⁇ )alkyl or (C-
  • Ra and Rb are independently H or (C ⁇ -C3)alkyl, wherein the (C-j- C3)alkyl includes both straight and branched chain radicals of up to 3 carbon atoms; or
  • A is a six membered carbocyclic ring and Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed five to seven membered carbocyclic ring, wherein the carbocyclic ring can optionally be substituted with one to three substituent(s) each independently being OH, halogen, (C ⁇ -C ⁇ )alkyl, (C-
  • Another possible subgroup of the compound of formula II is a compound of formula IIC,
  • R-) , R2, R3, R4, R5, R-] o> Rl 1 > m and t are as defined in formula II; i is 1 or 2; and j is 0 to 3.
  • Another possible subgroup of the compound of formula II is a compound of formula IID, wherein R-
  • the compound is 2- ⁇ 4-[4-(Acridin-9-yl)aminophenyl]piperazin-1-yl ⁇ - ethanol, (4-Methoxyacridin-9-yl)-[4-(4-methylpiperazin-1-yl)-phenyl]amine, Acridin-9-yl-[4-(piperidin-1 -yl)phenyl]amine, Acridin-9-yl-[4-(4-benzylpiperazin-1 - yl)phenyl]amine, Acridin-9-yl-[4-(4-methylpiperidin-1 -yl)phenyl]amine, Acridin-9- yl-[4-(3-hydroxymethylpiperidin-1 -yl)-phenyl]amine, Achdin-9-yl-[4-pyrrolidin-1 - yl)phenyl]amine, Acridin-9-yl-[4-(4-cyclopropylpiperazin-1-yl)phenyl
  • R ⁇ is (C-
  • the compounds of the invention may have chiral carbon atom(s) in their structure.
  • the invention includes within its scope all the possible stereoisomers of the compounds, including geometric isomers, e.g. Z and E isomers (cis and trans isomers), and optical isomers, e.g. diastereomers and enantiomers.
  • the invention includes in its scope both the individual isomers and any mixtures thereof, e.g. racemic mixtures.
  • the individual isomers may be obtained using the corresponding isomeric forms of the starting material or they may be separated after the preparation of the end compound according to conventional separation methods. For the separation of, for example, optical isomers, e.g. enantiomers, from the mixture thereof the conventional resolution methods, e.g. fractional crystallisation, may be used.
  • Physiologically acceptable salts e.g. acid addition salts with both organic and inorganic acids are well known in the field of pharmaceuticals.
  • Non-limiting examples of these salts include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates and ascorbates.
  • Pharmaceutically acceptable esters when applicable, may be prepared by known methods using pharmaceutically acceptable acids that are conventional in the field of pharmaceuticals and that retain the pharmacological properties of the free form.
  • Non-limiting examples of those esters include esters of aliphatic or aromatic alcohols, e.g. lower alkyl esters, e.g. methyl, ethyl and propyl esters.
  • a halogen or halo refers to fluorine, chlorine, bromine or iodine, e.g. fluorine or chlorine.
  • -C ⁇ )alkyl as employed herein as such or as part of another group includes both straight, and branched chain radicals of up to 6 carbon atoms, for example of 1 to 4 carbon atoms, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or s- butyl.
  • the term (C ⁇ -C ⁇ )alkoxy as such or as part of another group refers to -O-
  • C ⁇ )alkenyl includes both straight and branched chain radicals of up to 6 carbon atoms, for example of 2 to 4 carbon atoms, containing (a) double bond(s).
  • (C2-C ⁇ )alkynyl includes both straight and branched chain radicals of up to 6 carbon atoms, for example of 2 to 4 carbon atoms, containing (a) triple bond(s).
  • -C ⁇ )alkyl refers to (C-
  • C ⁇ )alkylcarbamoyl refers to a carbamoyl radical which is N-substituted with one or two (C- ⁇ -C ⁇ )alkyl radical(s), as defined above.
  • the compounds of the invention can be prepared analogously or according to a variety of synthetic routes known in the literature using suitable starting materials, for example, according to or analogous to methods described by 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, the contents of which are hereby incorporated by reference.
  • the compounds of the invention can be prepared e.g. analogously or according to the following reaction scheme 1 :
  • , R2, R3, R4, R5, m and t are as defined above.
  • the above reaction is a conventional acid-catalyzed coupling of the chloro-compound of formula III with a substituted aromatic amine of formula IV.
  • the reaction is carried out at room or elevated temperature in a suitable solvent, e.g. alcohol, such as methanol, in acidic conditions, to obtain the compound of formula I' which is then isolated from the reaction mixture in a usual manner.
  • a suitable solvent e.g. alcohol, such as methanol
  • the starting compounds III and IV are commercially available or can be prepared according to or analogously to the methods described in the literature (see e.g. J.Med.Chem., vol.20(8), 1977, pp. 987-996, and J.Med.Chem., vol.25,
  • a substituted aromatic NR ⁇ -amine IV can e.g. be prepared starting from the corresponding nitro compound which is reduced with a reducing agent, e.g. in the presence of SnCl2-H2O, in a suitable solvent, e.g. DMF, and optionally alkylated with R-
  • in a manner known in the art, when Ri (C-
  • a reducing agent e.g. in the presence of SnCl2-H2O
  • a suitable solvent e.g. DMF
  • the starting mate ⁇ al III can be prepared e.g. according to following scheme 2:
  • Ra, Rb, R3, and m are as defined above.
  • any starting material or intermediate can be protected, if necessary, in a manner well known in the chemical field. Any protected functionality can subsequently be deprotected in a manner known in the art.
  • the compounds of the invention may be converted, if desired, into their pharmaceutically acceptable salt or ester form using methods well known in the art.
  • the following examples are meant only for illustrating purposes and does not limit the scope of the invention defined in claims.
  • reaction mixture was then evaporated to dryness and purified by chromatography (silica gel column; gradient from 100 % methylene chloride to 90 % methylene chloride and 10 % methanol; when 4-(4-methylpiperazin-1-yl)aniline eluted from the column, the eluent was changed to methylene chloride : methanol : triethylamine 94 : 5 : 1 ). A final amount of 0.126 g (34 %, overall yield 12 %) of the title compound in pure form was obtained.
  • Example 16 Following the procedure outlined in Step 1 of Example 1 , but substituting 9-[4-(piperazin-1-yl)phenyl]aminoacridine (Example 16) for N-(4- nitrophenyl)piperazine, and benzyl bromide for methyl iodide, afforded the title compound (15 %, overall yield 2 %).
  • Example 16 Following the procedure outlined in Step 1 of Example 1 , but substituting 9-[4-(piperazin-1-yl)phenyl]aminoacridine (Example 16) for N-(4- nitrophenyl)piperazine, and isopropyl iodide for methyl iodide, afforded the title compound (11 %, overall yield 2 %).
  • the compounds of the invention show interesting pharmacological properties, namely, they exhibit antagonistic affinity for alpha-2 adrenoceptors. This activity is demonstrated in the pharmacological tests presented below.
  • the affinity of test compounds for the three human alpha-2-adrenoceptor subtypes was determined in binding competition assays with ⁇ H-rauwolscine.
  • the biological material consisted of membranes from Shionogi S115 cells stably transfected with one of the three human alpha-2 subtypes (A. Marjamaki et al., Biochem. Biophys. Acta, vol.1134, 1992, p.169).
  • the membrane suspension (about 10 ⁇ g total protein per sample) and 1 nM of ⁇ H-rauwolscine (specific activity 75-85 Ci/mmol) were incubated with a minimum of six concentrations of the test compound in a total volume of 90 ⁇ l (50 mM KH2PO4, pH 7.5, at room temperature).
  • Non-specific binding was defined by 100 ⁇ M oxymetazoline and corresponded to 4-10 % of the total binding.
  • the incubation was terminated by rapid filtration (TomTec 96 harvester) through presoaked GF/B glass-fiber mats (Wallac Oy) and three washes with ice-cold 50 mM KH2PO4 (pH 7.5, at room temperature). After drying, a solid scintillate (Meltilex; Wallac
  • alpha-2A Adrenoceptor 3150 ⁇ 50 nM
  • alpha-2B Adrenoceptor 1470 ⁇ 130 nM
  • alpha-2C Adrenoceptor 28 ⁇ 2 nM
  • Antagonist activity was determined as the ability of compounds to competetively inhibit epinephrine-stimulated 35s-GTP ⁇ S binding to G proteins (J.R. Jasper et al., Biochem. Pharmacol., vol.55, 1998, p.1035) in membranes of CHO cells stably transfected with one of the three human alpha-2 subtypes (K. Pohjanoksa et al., Eur. J. Pharmacol., vol.335, 1997, p.53).
  • Membranes (5- 10 ⁇ g of protein per sample) and 12 concentrations of test compound were preincubated for 30 min at room temperature in 50 mM Tris, 5 mM MgCI2, 150 mM NaCI, 1 mM DTT, 1 mM EDTA, 10 ⁇ M GDP, 30 ⁇ M ascorbic acid, pH 7.4, with a fixed concentration of epinephrine (5 ⁇ M for alpha-2A, 15 ⁇ M for alpha- 2B, 5 ⁇ M for alpha-2C). Then trace amounts of 35 S-GTP ⁇ S (0.08 nM- 0.15 nM, specific activity 1250 Ci/mmol) were added to the incubation mixture.
  • alpha-2A Adrenoceptor 1495 ⁇ 270 nM
  • alpha-2B Adrenoceptor 2175 ⁇ 345 nM
  • alpha-2C Adrenoceptor 16 ⁇ 6 nM
  • EXPERIMENT III Antagonism of dexmedetomidine -induced locomotor inhibition by atipamezole but not by Compound 1 ; demonstration of in vivo alpha2C selectivity of Compound 1
  • Dexmedetomidine and atipamezole are very potent and specific alpha-2 adrenoceptor agonists and antagonists, respectively, which lack alpha-2 subtype selectivity (H. Scheinin et al., European Journal of Pharmacology, Molecular Section, vol.151 (1 ), 1988, p.35-42).
  • the aipha-2 agonist -induced sedation is known to be an alpha-2A -mediated phenomenon that can be antagonised by alpha-2 antagonists (J. Sallinen et al., Mol. Pharmacol. Vol.51 , 1997, p.36-46, and A. Haapalinna et al., Naunyn-Schimiedeberg's Arch. Pharmacol.
  • an increase in the forced swimming activity can be used as a measure of in vivo alpha-2C selective antagonism of a compound.
  • the non-selective antagonist atipamezole did not have a clear stress-protective effect and even increased vocalizations of test animals (T. Kauppila et al., Eur. J. Pharmacol., vol.205, 1991 , p.177-182). This may have resulted from the simultaneous alpha-2A antagonistic activity of atipamezole, since conventionally non-selective alpha-2 adrenoceptor antagonists, such as yohimbine, have been found to be anxiogenic (S. Southwick et al., Arch. Gen. Psychiatry, vol.54, 1997, p.749- 758).
  • the forced swim test was conducted as originally described employing the stress sensitive (J. Crawley and L. Davis, Brain Research Bulletin, vol.8, 1982, p.609-612, and US-A-5 902 807) Balb/c mouse strain (B&K, Sweden).
  • the mice were administered either with vehicle (0.1 % DMSO, 5 ml/kg subcutaneously), Compound 1 0.3 ⁇ mol/kg, or atipamezole 0.3 ⁇ mol/kg 40 min before putting the mice into a vessel (10 cm diameter, 18.5 cm height, filled with 25°C water up to 8 cm height).
  • the cumulative activity of each mouse was measured between 2 and 6 min after introduction to the vessel. Only vigorous attempts to escape (climbing) were registered.
  • the mice (a total of 96) were tested only once. The results are shown in Figure 2.
  • a possible marginal effect of atipamezole was expected, since this subtype-non-selective alpha-2 antagonist blocks also the alpha-2C adrenoceptors.
  • the employed 0.3 ⁇ mol/kg dose of atipamezole was shown to have also alpha2A antagonism in vivo ( Figure 1 ).
  • atipamezole The employed doses of atipamezole have also been shown to have clear neurochemical effects, i.e. to stimulate noradrenaline release in brain (A. Haapalinna et al., Naunyn-Schimiedeberg's Arch. Pharmacol. Vol.356, 1997, p.570-582). Therefore, the results support that alpha-2A adrenoceptor antagonism of atipamezole can counteract the stress- protective and antidepressant effects of alpha-2C antagonism in vivo (J. Sallinen et al., Mol. Psychiatry, vol.4, 1999, p.443-452, and US-A-5 902 807).
  • the compounds of the invention exhibiting alpha-2 adrenoceptor antagonistic activity may be useful for the treatment of diseases or conditions wherein alpha-2 antagonists are effective.
  • the compounds can be used to treat disorders of the central nervous system, male sexual impotence, orthostatic hypotension, non-insulin dependent diabetes, and obesity, for example, disorders of the central nervous system.
  • the compounds can also be used to reverse effects induced by alpha-2 agonists.
  • Disorders of the central nervous system treatable with the compounds of the invention include depression, anxiety, post traumatic stress disorder, schizophrenia, Parkinson's disease, and other movement disorders.
  • the selective alpha-2C antagonists of the present invention may be used for the treatment of various diseases or conditions of CNS-system where alpha2C-antagonists are indicated to be beneficial (see e.g. US-A-5 902 807, J. Sallinen et al., Neuroscience, vol. 86, 1998, p.959-965, J. Sallinen et al., J. Neurosci., vol.18, 1998, p.3035-3042, and M. Bjorklund et al., Molecular 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.
  • the present alpha-2C antagonists can be used as stress-protective agents, or as agents for the treatment of CNS-disorders induced by stress, e.g. of post-traumatic stress disorder, as indicated, for example, in US-A-5 902 807 cited above. Because alpha-2C antagonists appear to stimulate central dopaminergic activity, they can be used as antiparkinsonian agents in Parkinson's disease and other movement disorders. Moreover, the present alpha-2C antagonists may also exhibit cognition enhancing properties and thus may be used in the treatment of Alzheimer's disease and other dementias.
  • the alpha-2C antagonists of the invention Due to the selectivity of tissue distribution, the alpha-2C antagonists of the invention have less or no undesirable side-effects, such as cardiovascular effects.
  • the compounds of the invention may be administered enterally, topically or parenterally.
  • the compounds of the invention may be formulated alone or together with another active ingredient and/or together with a pharmaceutically acceptable diluent, carrier and/or excipient in different pharmaceutical unit dosage forms, e.g. tablets, capsules, solutions, emulsions and powders etc., depending on the route of adminstration, using conventional techniques.
  • a pharmaceutically acceptable diluent, carrier and/or excipient can be selected from those conventionally used in the field of pharmaceuticals noticing the chosen route of administration.
  • the amount of the active ingredient in a dosage form may vary from, for example, 0.01 to 75 weight-% depending on, for example, the type of the dosage form.
  • the specific dose level of the compounds of the invention depends on several factors such as the compound to be administered, the species, age and the sex of the subject to be treated, the condition to be treated and on the route and method of administration. Accordingly, the dosage for parenteral administration is typically from 0.5 ⁇ g/kg to 10 mg/kg per day and that for oral administration is from 5 ⁇ g/kg to 100 mg/kg for an adult male.
  • the present invention further provides a compound of the invention for use as alpha-2 antagonist.
  • a method for the treatment of diseases or conditions where alpha-2 antagonists, e.g. alpha-2C antagonists, are indicated to be useful e.g. a method for the treatment of diseases or conditions of the central nervous system.
  • a therapeutically effective amount of a compound of the invention is administered to a subject in need of such treatment.
  • the use of the compounds of the invention for the manufacture of a medicament to be used for the above indications is also provided.

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