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SK13092000A3 - Glycine transport inhibitors - Google Patents

Glycine transport inhibitors Download PDF

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Publication number
SK13092000A3
SK13092000A3 SK1309-2000A SK13092000A SK13092000A3 SK 13092000 A3 SK13092000 A3 SK 13092000A3 SK 13092000 A SK13092000 A SK 13092000A SK 13092000 A3 SK13092000 A3 SK 13092000A3
Authority
SK
Slovakia
Prior art keywords
formula
alkyl
hydrogen
aryl
radical
Prior art date
Application number
SK1309-2000A
Other languages
Slovak (sk)
Inventor
Walter Herman Maria Louis Luyten
Frans Eduard Janssens
Ludo Edmond Josephine Kennis
Original Assignee
Janssen Pharmaceutica N. V.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Janssen Pharmaceutica N. V. filed Critical Janssen Pharmaceutica N. V.
Publication of SK13092000A3 publication Critical patent/SK13092000A3/en

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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
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    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract

The present invention is concerned with the use of glycine transport inhibiting alpha , alpha -diphenyl-1-piperidinebutanamides for the preparation of medicaments for treating disorders of the central and peripheral nervous system, in particular psychoses, pain, epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head trauma, multiple sclerosis and the like. The invention further comprises novel compounds, their preparation and their pharmaceutical forms.

Description

Predkladaný vynález sa týka využitia α,α-difenyl-lpiperidínbutánamidu inhibujúceho prenos glycínu na prípravu liekov pre liečbu porúch centrálneho a periférneho nervového systému, predovšetkým psychózy, bolestivých stavov, epilepsie, neurodegeneratívnych chorôb (Alzheimerova choroba), mozgovej príhody, úrazov hlavy, roztrúsenej sklerózy apod. Vynález dalej zahŕňa nové zlúčeniny, ich prípravu a farmaceutické formy.The present invention relates to the use of α, α-diphenyl-1-piperidine-butanamide inhibiting glycine transfer for the preparation of medicaments for the treatment of central and peripheral nervous system disorders, particularly psychosis, pain conditions, epilepsy, neurodegenerative diseases (Alzheimer's), stroke, trauma, head trauma etc. The invention further encompasses novel compounds, their preparation and pharmaceutical forms.

N,//-dimetyl—α,α-difenyl-l-piperidínbutánamidy, ako napríklad 4- (4-chlórf enyl) -4 -hydroxy-N, JV-dimetyl-α, a-difenyl-1piperidínbutánamid (loperamid, Imodium™), sú známe protihnačkové látky. Podstata týchto látok, ich príprava a účinky sa poprvýkrát objavili v patente US - 3,714,159.N, N -dimethyl-α, α-diphenyl-1-piperidinobutanamides such as 4- (4-chlorophenyl) -4-hydroxy-N, N -dimethyl-α, α-diphenyl-1-piperidinebutanamide (loperamide, Imodium ™ ), antifungal agents are known. The essence of these substances, their preparation and effects were first disclosed in US-3,714,159.

Predkladaný vynález sa zaoberá využitím zlúčenín inhibujúcich transport glycínu na liečbu porúch centrálneho a periférneho nervového systému. Tieto zlúčeniny majú vzorecThe present invention is directed to the use of glycine transport inhibiting compounds for the treatment of central and peripheral nervous system disorders. These compounds have the formula

Ide o stereochemické izoméry JV-oxidov a na farmaceutické účely vhodné adičné soli, kdeThese are the stereochemical isomers of the N -oxides and pharmaceutically acceptable addition salts thereof

R1 a R2 nezávisle od seba predstavujú vodíky alebo alkylyR 1 and R 2 independently represent hydrogen or alkyl

Cx až C4;C x to C 4 ;

ŕà

X predstavuje substituent vzorcaX represents a substituent of the formula

/CXR5 (b) kde čiarkovaná čara predstavuje lubovolnú väzbu; predstavuje substituent vzorca / CX R 5 (b) wherein the dotted line represents any bond; represents a substituent of the formula

v ktorom každý zo substituentov R6 a R7 je vodík alebo sa obidva dohromady spoja s dvoma atómami uhlíka za vzniku fenylu;wherein each of R 6 and R 7 is hydrogen or both are taken together with two carbon atoms to form phenyl;

R8 predstavuje vodík alebo halogén;R 8 represents hydrogen or halogen;

n je 1 alebo 2;n is 1 or 2;

R4 predstavuje vodík, hydroxyskupinu, C1-4 alkyloxyskupinu, C1_4 alkyloxy C1_4 alkyl alebo aryl C1-4 alkyloxyskupinu;R 4 is hydrogen, hydroxy, C 1-4 alkyloxy, C 1 _ 4 alkyloxy C 1 _ 4 alkyl or aryl C 1-4 alkyloxy;

R5 predstavuje diarylmetyloxy C1-4 alkyl alebo substituent vzorcaR 5 represents a diarylmethyloxy C 1-4 alkyl or a substituent of the formula

N (b-1)N (b-1)

(b-2)(B-2)

kde B1 predstavuje -CH2, -CH(OH)-, -NH-, -CH2-NH- alebo priamu väzbu;wherein B 1 represents -CH 2 , -CH (OH) -, -NH-, -CH 2 -NH- or a direct bond;

B2 predstavuje -NH-, -CH2- alebo priamu väzbu B3 predstavuje -NR12-, -CH2“, -C(=O)- alebo priamu väzbu B7 predstavuje -cy_4 alkándiyl-NH- alebo -NH-C^-^alkyl-;B 2 represents -NH-, -CH 2 - or a direct bond B 3 represents -NR 12 -, -CH 2 -, -C (= O) - or a direct bond B 7 represents -c 1-4 alkanediyl-NH- or -NH-C ^ - ^ alkyl;

B8 predstavuje -NR19-, -CH2- alebo -CH(aryl)-;B 8 is -NR 19 -, -CH 2 -, or -CH (aryl) -;

Y predstavuje vždy nezávisle od seba atóm 0 alebo S; -a1=a2-a3=a4- predstavuje dvojväzný substituent vzorcaY is independently O or S; -a 1 = a 2 -a 3 = a 4 - represents a divalent substituent of the formula

-CH=CH-CH=CH- (b-l-a) alebo-CH = CH-CH = CH- (b-1-a) or

-N=CH-N=CH- (b-l-b);-N = CH-N = CH- (b-1-b);

pričom vodíkový atóm v substituente (b-l-a) môže byt nahradený hydroxyskupinou;wherein the hydrogen atom in the substituent (b-1-a) may be replaced by a hydroxy group;

R9 predstavuje C1-4 alkyl, alebo C1-4 alkyl substituovaný arylom, tienylom, furanylom, furanylom substituovaným hydroxy Cj_4 alkylom alebo tiazolylom;R 9 is C 1-4 alkyl, or C 1-4 alkyl substituted with aryl, thienyl, furanyl, furanyl substituted with hydroxy C 1-4 alkyl or thiazolyl;

R10 predstavuje aryl, arylaminoderivát, cl-4 alkylaminoderivát, Cj_4 alkyltioderivát;R 10 is aryl, arylamino, C l-4 alkylaminoderivát, Cj_ 4 alkylthio derivative;

R11 predstavuje vodík, C1-4 alkyl, halogén- alebo trifluormetyl;R 11 represents hydrogen, C 1-4 alkyl, halogen- or trifluoromethyl;

R12 predstavuje vodík alebo C1-4 alkylkarbonyl;R 12 represents hydrogen or C 1-4 alkylcarbonyl;

R13 predstavuje vodík, C1-4 alkyl alebo aryl;R 13 represents hydrogen, C 1-4 alkyl or aryl;

R14 predstavuje vodík alebo halogénderivát;R 14 represents hydrogen or a halogen derivative;

R15 a R16 nezávisle od seba predstavujú vodík alebo aryl; R17 predstavuje vodík alebo Cj_4 alkyl;R 15 and R 16 independently represent hydrogen or aryl; R 17 represents hydrogen or C 1-4 alkyl;

R18 predstavuje aryl,R 18 represents aryl,

10,ll-dihydro-5/f-dibenz[b,f]azepin-5-yl alebo C1-4 alkyl volne substituovaný jedným alebo dvoma od seba nezávislými substituentmi tvorenými C3_7 cykloalkylom alebo arylom;10, ll-dihydro-5 / f-dibenzo [b, f] azepin-5-yl or C 1-4 alkyl freely bears one or two substituents each independently formed by C 3 _ 7 cycloalkyl or aryl;

R19 predstavuje vodík, C1-4 alkylkarbonyl alebo diaryl 01-4 alkyl;R 19 represents hydrogen, C 1-4 alkylcarbonyl or diaryl O 1-4 alkyl;

R20, R21, R22 a R23 nezávisle od seba predstavujú vodík, α1-4 alkyl alebo aryl;R 20 , R 21 , R 22 and R 23 independently represent hydrogen, α 1-4 alkyl or aryl;

R24 predstavuje vodík alebo trifluormetyl;R 24 represents hydrogen or trifluoromethyl;

R25 predstavuje vodík alebo halogén; a v prípade, že radikál R5 má vzorec (b-3), môže R4 byt tiež fenyl C1-4 alkylaminokarbonyl; aR 25 represents hydrogen or halogen; and when the radical R 5 has the formula (b-3), R 4 can also be phenyl C 1-4 alkylaminocarbonyl; and

R4 a R5 môžu spoločne vytvoriť spiroradikál vzorcaR 4 and R 5 together can form a spiroradical of the formula

(b-14) kde R26 a R27 nezávisle od seba predstavujú vodík, C^_4 alkyl, aryl alebo aryl C1_4alkyl;(b-14) wherein R 26 and R 27 independently represent hydrogen, C ^ _ 4 alkyl, aryl or aryl C 1 _ 4 alkyl;

aryl je v tomto prípade fenyl alebo fenyl substituovaný jedným alebo dvoma substituentmi nezávisle od seba tvorenými C-j^ alkylom, halogénderivátom, hydroxyskupinou a Cj_4 alkyloxylom.aryl in this case is phenyl or phenyl substituted by one or two substituents independently of one another consisting of C 1-4 alkyl, halo derivative, hydroxy and C 1-4 alkyloxy.

Predkladaný vynález tiež súvisí s metódou liečby teplokrvných zvierat trpiacich poruchami centrálneho a periférneho nervového systému, predovšetkým psychózy, bolestivých stavov, epilepsie, neurodegeneratívnych chorôb (Alzheimerova choroba), mozgovej príhody, úrazov hlavy, roztrúsenej sklerózy apod. Uvedená metóda obsahuje rozpis terapeuticky efektívneho množstva zlúčeniny (I) alebo A-oxidovej formy a farmaceutický vhodnej kyslej alebo zásaditej adičnej soli alebo jej stereoizoméru v kombinácii s farmaceutickým nosičom.The present invention also relates to a method of treating warm-blooded animals suffering from central and peripheral nervous system disorders, in particular psychosis, pain conditions, epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head trauma, multiple sclerosis and the like. Said method comprises the breakdown of a therapeutically effective amount of compound (I) or the A-oxide form and a pharmaceutically acceptable acid or base addition salt or stereoisomer thereof in combination with a pharmaceutical carrier.

Vo vzorcoch opisovaných v predkladanom vynáleze je halogén všeobecné označenie pre fluór, chlór, bróm a jód;In the formulas described herein, halogen is generic to fluoro, chloro, bromo and iodo;

C4_7 alkyl je cyklobutyl, cyklopentyl, cyklohexyl a cykloheptyl;C 4 _ 7 alkyl are cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;

cl-4 definuje priame a rozvetvené reťazce nasýtených uhľovodíkových zvyškov s 1 až 4 uhlíkovými atómami, ako napríklad metyl, etyl, propyl, butyl, 1-metyletyl, 2-metylpropyl, 2,2-dimetyletyl a iné; C1-4 alkándiyl definuje dvojväzné priame a rozvetvené reťazce nasýtených uhľovodíkových zvyškov, ktoré majú 1 až 4 uhlíkové atómy, ako napríklad C l-4 defines straight and branched chain saturated hydrocarbon radicals having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the other; C 1-4 alkanediyl defines divalent straight and branched chains of saturated hydrocarbon radicals having 1 to 4 carbon atoms, such as

1.1- metándiyl, 1,2-etándiyl, 1,3-propándiyl, 1,4-butándiyl,1,1-methanediyl, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl,

1.2- propándiyl, 2,3-butándiyl a iné.1,2-propanediyl, 2,3-butanediyl and others.

Uvedené adičné soli vhodné na farmaceutické účely predstavujú terapeuticky aktívne netoxické formy zásaditých a kyslých adičných solí, ktoré môžu tvoriť zlúčeniny vzorca (I). Zlúčeniny (I) vyskytujúce sa vo voínej forme ako bázy, sa menia na kyslú adičnú sol reakciou príslušnej bázy s vhodnou anorganickou kyselinou, napríklad halogenovodíkovou (chlorovodíkovou alebo bromovodíkovou), sírovou, dusičnou, prípadne fosforečnou, alebo organickou, ako napríklad octovou, hydroxyoctovou, propánovou, mliečnou, pyrohroznovou, šťavelovou, malónovou, jantárovou, maleínovou, fumarovou, jablčnou, vínnou, citrónovou, metánsulfónovou, etánsulfónovou, benzénsulf ónovou, p-toluénsulfónovou, N-cyklohexylsulfámovou, salycilovou, p-aminosalycilovou a inými.Said addition salts suitable for pharmaceutical purposes are the therapeutically active non-toxic forms of the basic and acid addition salts which may form the compounds of formula (I). Compounds (I) occurring in free form as a base are converted to an acid addition salt by reacting the corresponding base with a suitable inorganic acid, for example, hydrohalic (hydrochloric or hydrobromic), sulfuric, nitric, or phosphoric, or organic, such as acetic, hydroxyacetic, propane, milky, pyruvic, oxalic, malonic, amber, maleic, fumaric, apple, tartar, lemon, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, N-cyclohexylsulfamic, and salycilium, p-toluenesulfonic, salycil.

Zlúčeniny vzorca (I) obsahujúce kyslé protóny sa menia na terapeuticky aktívne netoxické bázy, tzn. kov alebo amín, reakciou so zodpovedajúcou organickou a anorganickou bázou. Medzi vhodné bázické soli patria napríklad amónne soli, soli alkalických kovov a kovov alkalických zemín, čiže lítne, sodné draselné, horečnaté, vápenaté soli a podobne. Zo solí obsahujúcich organickú bázu sa uvádza napríklad benzatín, 27-metylD-glukozamín, hydráty aminosolí a soli s aminokyselinami, napríklad arginínom, lyzínom a podobne.Compounds of formula (I) containing acidic protons are converted into therapeutically active non-toxic bases, i. metal or amine, by reaction with the corresponding organic and inorganic bases. Suitable base salts include, for example, ammonium salts, alkali metal and alkaline earth metal salts, i.e. lithium, sodium potassium, magnesium, calcium salts and the like. Among the salts containing the organic base, mention may be made, for example, of benzatin, 27-methyl-D-glucosamine, amino acid hydrates and salts with amino acids such as arginine, lysine and the like.

Obrátene, tieto soli sa premenia do voínej formy reakciou so zodpovedajúcou bázou alebo kyselinou.Conversely, these salts are converted into the free form by reaction with the corresponding base or acid.

Výraz adičná sol, ktorý sa v texte používa, zahŕňa tiež solváty zlúčenín (I) a ich solí, napríklad hydráty, alkoholáty a iné.The term addition salt as used herein also includes solvates of compounds (I) and their salts, for example hydrates, alcoholates and others.

ΑΓ-oxidová forma zlúčenín vzorca (I) predstavuje súhrn tých zlúčenín vzorca (I), v ktorých je atóm dusíka v piperidíne oxidovaný na JV-oxid.The ΓΓ -oxide form of the compounds of formula (I) represents the sum of those compounds of formula (I) in which the nitrogen atom in the piperidine is oxidized to the N-oxide.

Termín stereochemické izoméry sa používa na označenie všetkých možných stereoizomérnych foriem zlúčenín (I). Pokial to nie je uvedené inak, chemické označenie (názov) zlúčenín označuje zmesi, predovšetkým racemické zmesi vo všetkých možných stereochemických formách, inak povedané, zmesi obsahujúce všetky diastereoméry a enantioméry základnej molekulovej štruktúry. Je zrejmé, že vzorec (I) zahŕňa všetky stereoizoméry zlúčenín (I) a ich zmesi.The term stereochemical isomers is used to refer to all possible stereoisomeric forms of the compounds (I). Unless otherwise stated, the chemical designation of the compounds refers to mixtures, especially racemic mixtures in all possible stereochemical forms, in other words, mixtures containing all diastereomers and enantiomers of the basic molecular structure. It will be understood that formula (I) includes all stereoisomers of compounds (I) and mixtures thereof.

Zlúčeniny vzorca (I) a niektoré ich medziprodukty majú v svojej štruktúre aspoň jedno stereogénne centrum. Toto centrum sa označuje ako R alebo S konfigurácia, v súlade s pravidlami opísanými v Pure Appl. Chem., 1976, 45, 11-30.The compounds of formula (I) and some of their intermediates have at least one stereogenic center in their structure. This center is referred to as the R or S configuration, according to the rules described in Pure Appl. Chem., 1976, 45, 11-30.

Niektoré zo mérnych formách. (I), zahŕňajú sa zlúčenín vzorca (I) môžu existovať v tautoHoci tieto formy nezodpovedajú presne vzorcu do oblasti predkladaného vynálezu.Some of the meager forms. (I), the compounds of formula (I) included may exist in this form, although these forms do not exactly correspond to the formula within the scope of the present invention.

Ako už bolo povedané, termínom zlúčenina vzorca (I) sú označené tiež W-oxidy, farmaceutický vyhovujúce adičné soli a všetky stereoizomérne formy. O novom zložení zlúčenín (I) sa uvažuje v nasledujúcich prípadoch; ked R4 je vodík a R5 substituent vzorca (b-1), kde B1 je -CH2- a R9 je 4-fluorobenzyl, potom -a1=a2-a3=a4- je odlišné od -CH=CH-CH=CHa ked R4 je vodík a R5 je substituent vzorca (b-1), kde B1 je -NH- a R9 je 4-metoxybenzyl, potom -a1=a2-a3=a4- je odlišné od -CH=N-CH=N-. Predkladaný vynález sa vzťahuje tiež na využitie nových typov zlúčenín (I) ako liekov.As already mentioned, the term compound of formula (I) also refers to N-oxides, pharmaceutically acceptable addition salts and all stereoisomeric forms. A new composition of compounds (I) is contemplated in the following cases; when R 4 is hydrogen and R 5 is a substituent of formula (b-1), wherein B 1 is -CH 2 - and R 9 is 4-fluorobenzyl, then -a 1 = a 2 -a 3 = a 4 - is different from - CH = CH-CH = CHa when R 4 is hydrogen and R 5 is a substituent of formula (b-1) wherein B 1 is -NH- and R 9 is 4-methoxybenzyl, then -a 1 = and 2 -a 3 = and 4 - is different from -CH = N-CH = N-. The present invention also relates to the use of new types of compounds (I) as medicaments.

R5 je zvyčajne diarylmetyloxy C1-4 alkyl alebo substituent vzorca (b-2), (b-3), (b-4), (b-5), (b-6), (b—7), (b-8), (b-9), (b-10), (b-11), (b-12) alebo (b-13), prípadne R5 môže spoločne s R4 vytvoriť spiroradikál vzorca (b-14).R 5 is generally diarylmethyloxy C 1-4 alkyl or a substituent of formula (b-2), (b-3), (b-4), (b-5), (b-6), (b-7), ( b-8), (b-9), (b-10), (b-11), (b-12) or (b-13), optionally R 5 may form together with R 4 a spiroradical of formula (b-14) ).

Zaujímavou skupinou sú zlúčeniny vzorca (I), kde R1 a R2 tvoria metylové skupiny.An interesting group are compounds of formula (I) wherein R 1 and R 2 form methyl groups.

Medzi dôležité zlúčeniny vzorca (I) patria tie, kde X predstavuje substituent vzorca (a), najmä vtedy, kedf sú vo vzorci (a) R6 a R7 spojené dvoma atómami uhlíka za vzniku fenylu.Important compounds of formula (I) include those wherein X represents a substituent of formula (a), especially when in formula (a), R 6 and R 7 are joined by two carbon atoms to form phenyl.

Ďalšími dôležitými zlúčeninami vzorca (I) sú tie, kde X predstavuje substituent vzorca (b), v ktorom R5 je substituent vzorca (b-1), ale predovšetkým, kde R9 je Cj_4 alkyl substituovaný arylom, najčastejšie 4-fluorobenzyl.Other important compounds of formula (I) are those wherein X represents a substituent of formula (b), wherein R 5 is a substituent of formula (b-1), but particularly where R 9 is aryl-substituted C 1-4 alkyl, most often 4-fluorobenzyl.

Poslednú dôležitú skupinu predstavujú tie zlúčeniny (I), v ktorých X je substituent vzorca (b), pričom R5 má vzorec (b-2), ale predovšetkým, v ktorých Y je zastúpené S.The last important group is represented by those compounds (I) in which X is a substituent of formula (b), wherein R 5 has the formula (b-2), but especially in which Y is represented by S.

Dôležitými zlúčeninami sú:Important compounds are:

4-(11,12-dihydro-6H-benzimidazo[ 2,1-b] [ 3 ]benzazepin-6-yl) N, N-dimetyl-α, a-dif enyl-l-piperidínbutánamid;4- (11,12-dihydro-6H-benzimidazo [2,1-b] [3] benzazepin-6-yl) - N, N-dimethyl-α, α-diphenyl-1-piperidinebutanamide;

4-[ [l-[ (4-f luórf enyl )metyl]-lH-benzimidazol-2-yl] hydroxymetyl ] -N, N-dimetyl-α, a-dif enyl-l-piperidínbutánamid;4 - [[1 - [(4-fluorophenyl) methyl] -1H-benzimidazol-2-yl] hydroxymethyl] -N, N-dimethyl-α, α-diphenyl-1-piperidinebutanamide;

N-oxidy, stereoizoméry a farmaceutický vhodné adičné soli.N-oxides, stereoisomers and pharmaceutically acceptable addition salts.

Doterajší stav technikyBACKGROUND OF THE INVENTION

Všeobecne sa zlúčeniny vzorca (I) pripravujú reakciami opi sanými V patentoch US-3,714,159, US-4,695,575 a US-5,008,268, ešte dôležitejšia je reakcia medziproduktu (II), kde W je vhodný ión, ako napríklad halogén alebo jeho funkčný derivát, s medziproduktom (III).In general, the compounds of formula (I) are prepared by the reactions described in US-3,714,159, US-4,695,575 and US-5,008,268, more importantly the reaction of intermediate (II) wherein W is a suitable ion such as halogen or a functional derivative thereof with the intermediate (III).

Reakcia uvedená na nasledujúcom obrázku môže prebiehal: v inertnom rozpúšťadle, akým je napríklad metylizobutylketón,The reaction shown in the following figure may take place: in an inert solvent such as methyl isobutyl ketone,

N, H-dimetylacetamid alebo N, H-dimetylformamid, v prítomnosti vhodnej bázy, napríklad uhličitanu sodného, hydrogénuhličitanu sodného, trimetylamínu alebo aj jodidu draselného, ktorý bol použitý práve v tomto vynáleze.N, H-dimethylacetamide or N, H-dimethylformamide, in the presence of a suitable base, for example sodium carbonate, sodium bicarbonate, trimethylamine or even potassium iodide, which has been used in the present invention.

V tejto aj v nasledujúcich prípravách sa reakčné produkty izolujú z reakčného prostredia a v prípade potreby sa ďalej čistia bežnými metódami, napríklad extrakciou, kryštalizáciou, destiláciou, rozmelnením a chromatograficky.In this and the following preparations, the reaction products are isolated from the reaction medium and, if necessary, further purified by conventional methods, for example, extraction, crystallization, distillation, comminution and chromatography.

Zlúčeniny (I) sa môžu vzájomne meniť známym procesom transformácie funkčných skupín.Compounds (I) may be mutually interchanged by a known functional group transformation process.

Zlúčeniny (I) sa môžu premeniť na zodpovedajúce A-oxidové formy prechodom trojmocného atómu dusíka na A-oxid; všeobecne dochádza k oxidácii reakciou východiskovej látky vzorca (I) s 3-fenyl-2-(fenylsulfonyl)oxaziridínom, prípadne vhodným organickým alebo anorganickým peroxidom. Vhodným anorganickým peroxidom je napríklad peroxid vodíka, peroxidy alkalických kovov alebo kovov alkalických zemín a iné; vhodnými organickými peroxidmi sú predovšetkým peroxokyseliny, napríklad benzénkarboperoxidová kyselina alebo jej halogénderiváty, ako 3-chlórbenzénkarboperoxidová kyselina, peroxoalkánové kyseliny, ako napríklad peroxooctová kyselina, alkylhydroperoxidy, napríklad t-butylhydroperoxid. Vhodnými rozpúšťadlami sú napríklad voda, nižšie alkanoly, ako etanol, uhíovodíky, napríklad toluén, ketóny, napríklad 2-butanón, halogénderiváty uhľovodíkov, ako napríklad dichlórmetán a zmesi týchto rozpúšťadiel .Compounds (I) can be converted to the corresponding A-oxide forms by transitioning the trivalent nitrogen atom to the A-oxide; in general, oxidation occurs by reaction of the starting material of formula (I) with 3-phenyl-2- (phenylsulfonyl) oxaziridine, optionally with a suitable organic or inorganic peroxide. Suitable inorganic peroxides are, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides and others; suitable organic peroxides are, in particular, peracids, for example benzenecarboperoxide acid or its halogen derivatives, such as 3-chlorobenzenecarboperoxide acid, peroxoalkanoic acids such as peroxoacetic acid, alkyl hydroperoxides, for example t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols such as ethanol, hydrocarbons such as toluene, ketones such as 2-butanone, halogenated hydrocarbon derivatives such as dichloromethane and mixtures of these solvents.

Niektoré zlúčeniny (I) a medziprodukty uvádzané v tomto vynáleze môžu obsahovať asymetrický uhlík. Čisté stereoizoméry uvedených zlúčenín a medziproduktov sa získavajú bežnými metódami; napríklad diastereoizoméry sa izolujú fyzikálnymi metódami, ako je selektívna kryštalizácia alebo chromatografické metódy, a to protiprúdové delenie, kvapalinová chromatografia a podobné metódy. Enantioméry sa získavajú z racemických zmesí najskôr ich premenou vhodnými rozpúšťadlami, ako sú chirálne kyseliny, na zmesi diastereoizomérnych solí alebo zlúčenín, potom nasleduje rozdelenie týchto zmesí alebo zlúčenín napríklad selektívnou kryštalizáciou alebo chromatograficky (kvapalinovou chromatografiou a inými metódami), a nakoniec sa premenia jednotlivé diastereoizomérne soli alebo iné zlúčeniny na zodpovedajúce enantioméry. Čisté stereochemické izoméry sa môžu získať tiež priamo z čistých stereoizomérnych foriem vhodných medziproduktov a východiskových látok tak, že príslušné reakcie prebiehajú stereošpecificky.Certain compounds (I) and intermediates of this invention may contain asymmetric carbon. Pure stereoisomers of said compounds and intermediates are obtained by conventional methods; for example, diastereoisomers are isolated by physical methods such as selective crystallization or chromatographic methods such as countercurrent resolution, liquid chromatography, and the like. Enantiomers are obtained from racemic mixtures by first converting them with suitable solvents such as chiral acids into mixtures of diastereoisomeric salts or compounds, followed by resolution of the mixtures or compounds by, for example, selective crystallization or chromatography (liquid chromatography and other methods), and finally converting the individual salts or other compounds to the corresponding enantiomers. Pure stereochemical isomers may also be obtained directly from the pure stereoisomeric forms of the appropriate intermediates and starting materials so that the respective reactions proceed stereospecifically.

K alternatívnym spôsobom rozdelenia enantiomérnych foriem zlúčenín (I) a medziproduktov patrí kvapalinová chromatografia, predovšetkým metóda využívajúca chirálne stacionárne fázy.Alternative methods for resolving enantiomeric forms of compounds (I) and intermediates include liquid chromatography, in particular a method employing chiral stationary phases.

Niektoré medziprodukty a východiskové látky sú známe, často komerčne dostupné alebo lahko pripravitelné látky.Some intermediates and starting materials are known, often commercially available or readily prepared substances.

Glycín je aminokyselina spôsobujúca ako inhibičný, tak excitačný prenos na nervových zakončeniach centrálneho a periférneho nervového systému. Táto jeho rozdielna funkcia je daná dvoma typmi receptorov, ktoré fungujú ako prenášače glycínu. Inhibičné účinky glycínu sú spôsobené receptormi citlivými na strychnín (alkaloid vyvolávajúci kŕče), preto sa na11 zývajú strychnín-senzitívne. Strychnín-senzitívne glycínové receptory sa nachádzajú predovšetkým v mieche a mozgovom kmeniGlycine is an amino acid that causes both inhibitory and excitatory transmission at the nerve endings of the central and peripheral nervous systems. This different function is due to two types of receptors that act as glycine transporters. The inhibitory effects of glycine are caused by strychnine-sensitive receptors (alkaloid-inducing convulsions) and therefore are called strychnine-sensitive. Strychnine-sensitive glycine receptors are found primarily in the spinal cord and brainstem

Pri excitačnom prenose funguje glycín ako regulátor pôsobenia glutamátu, hlavného neurotransmiteru v nervovom systému [John a Ascher: Náture, 325 (1987), 521 - 531; Fletcher et al: Glycine Transmission, Otterson and Storm-Matisen nakl. (1990), str. 193 - 219]. Glycín sa svojim charaktorom radí medzi tak zvané NMDA glycínové receptory (N-metyl-D-aspartát), ktoré sa nachádzajú vo veíkej miere v mozgu, predovšetkým v mozgovej kôre a hippocampu.In excitatory transfer, glycine functions as a regulator of glutamate, a major neurotransmitter in the nervous system [John and Ascher: Nature, 325 (1987), 521-531; Fletcher et al.: Glycine Transmission, Otterson, and Storm-Matisen nakl. (1990) p. 193-219]. Glycine, by its nature, ranks among the so-called NMDA glycine receptors (N-methyl-D-aspartate), which are found to a large extent in the brain, particularly in the cerebral cortex and hippocampus.

Prenášače glycínu regulujú koncentráciu a čas pôsobenia neurotransmiteru v nervových zakončeniach (synapsiách), čiže regulujú intenzitu synaptického prenosu. Okrem toho tiež udržujú presnost synaptického prenosu tak, aby nedošlo k rozšíreniu neurotransmiterov do susedných synapsií. Nakoniec, po prenose vzruchu sa synapsiami uvoínené transmitery ukladajú v presynaptickom zakončení a sú pripravené na ďalšie použitie. Prenos neurotransmiterov závisí od množstva mimobunkového sodíka a gradientu napätia na membráne. Za špecifických podmienok, napríklad pri záchvate, môžu prenášače fungovať obrátene tak, že uvoíňujú neurotransmitery v kalciumindependentných kanáloch [Attwell et al: Neurón, 11 (1993), 401 - 407]. Zmena prenášačov neurotransmiterov teda umožňuje upravovať synaptickú aktivitu, čo sa úspešne využíva pri liečbe porúch centrálneho a periférneho nervového systému.Glycine transporters regulate the concentration and time of action of the neurotransmitter in the nerve endings (synapses), thus regulating the intensity of synaptic transmission. In addition, they also maintain the accuracy of synaptic transmission so that neurotransmitters do not spread to adjacent synapses. Finally, after transmission of excitement, synapse-released transmitters are stored at the presynaptic end and are ready for further use. Transmission of neurotransmitters depends on the amount of extracellular sodium and the voltage gradient on the membrane. Under specific conditions, e.g., seizure, the transporters may function inversely to release neurotransmitters in calcium-dependent channels [Attwell et al: Neuron, 11 (1993), 401-407]. Thus, changing neurotransmitter transporters makes it possible to modulate synaptic activity, which is successfully used in the treatment of central and peripheral nervous system disorders.

Molekulové klonovanie odhalilo existenciu dvoch skupín glycínových prenášačov, nazývaných GlyT-1 a GlyT-2. GlyT-1 sa nachádza predovšetkým v prednom mozgu a jeho rozloženie korešponduje s dráhami glutamátu a NMDA receptorov [Smith et al: Neurón, 8 (1992), 927 - 935]. Dnes sú známe tri veími previazané varianty GlyT-1 označované ako GlyT-la, GlyT-lb a GlyT-lc [Kim et al: Molecular Pharmacology, 45 (1994), 608 - 617].Molecular cloning revealed the existence of two groups of glycine transporters, called GlyT-1 and GlyT-2. GlyT-1 is mainly found in the forebrain and its distribution corresponds to glutamate and NMDA receptor pathways [Smith et al: Neuron, 8 (1992), 927-935]. Three widely linked variants of GlyT-1, known as GlyT-1α, GlyT-1b and GlyT-1c, are known today [Kim et al: Molecular Pharmacology, 45 (1994), 608-617].

Každá z nich vykazuje ojedinelé rozmiestnenie v mozgu a periférnych tkanivách. Na rozdiel od týchto látok, GlyT-2 sa nachádza predovšetkým v mozgovom kmeni a mieche, a jeho rozmiest nenie je spojené so strychnín-senzitívnymi receptormi [Liu et al: J. Biological Chemistry, 268 (1993), 22802 - 22808; Jurský a Nelson: Neurochemistry, 64 (1995), 1026 - 1033]. Je možné preto očakávať, že pri regulácii synaptické hladiny glycínu GlyT-1 a GlyT-2 selektívne menia aktivitu NMDA receptorov, respektíve strychnín-senzitívnych receptorov.Each exhibits a unique distribution in the brain and peripheral tissues. In contrast, GlyT-2 is found primarily in the brainstem and spinal cord, and its distribution is associated with strychnine-sensitive receptors [Liu et al: J. Biological Chemistry, 268 (1993), 22802-22808; Jursky and Nelson: Neurochemistry, 64 (1995), 1026-1033]. It is therefore expected that, in regulating the synaptic levels of glycine, GlyT-1 and GlyT-2 selectively alter the activity of NMDA receptors and strychnine-sensitive receptors, respectively.

Predpokladá sa, že zlúčeniny inhibujúce alebo naopak aktivujúce prenášače glycínu upravujú funkciu receptoru, a tým sú užitočné pri liečbe rôznych ochorení. Napríklad potlačenie funkcie GlyT-2 znížením synaptickej hladiny glycínu vedie k poklesu aktivity neurónov so strychnín-senzitívnymi receptormi. Tým sa stlmí v mieche prenos bolestivej informácie, ktorú, ako sa ukázalo, práve tieto receptory sprostredkovávajú [Yaksh: Pain, 37 (1989), 111 - 123].Compounds inhibiting or activating glycine transporters are believed to modulate receptor function and are thus useful in the treatment of various diseases. For example, suppression of GlyT-2 function by decreasing synaptic glycine levels results in a decrease in the activity of neurons with strychnine-sensitive receptors. This inhibits the transmission of painful information in the spinal cord, which has been shown to be mediated by these receptors [Yaksh: Pain, 37 (1989), 111-123].

Navyše, zvýšením inhibičného prenosu strychnín-senzitívnymi receptormi v mieche sa využíva na zníženie svalovej hyperaktivity pri liečbe chorôb a stavov, kečí sa zvyšuje svalová kontrakcia, napríklad pri kŕčoch, myoklónii a epilepsii [ Truong et al: Movement Disorders, 3 (1988), 77 - 87; Becker: FASEB J., 4 (1990), 2767 - 2774].In addition, by increasing the inhibitory transmission of strychnine-sensitive receptors in the spinal cord, it is used to reduce muscle hyperactivity in the treatment of diseases and conditions where muscle contraction is increased, for example in convulsions, myoclonia and epilepsy [Truong et al: Movement Disorders, 3 (1988) 77 - 87; Becker: FASEB J., 4 (1990), 2767-2774].

Kŕčovité stavy, ktoré sa liečia zmenou glycínových receptorov, súvisia s epilepsiou, mozgovou mŕtvicou, úrazmi hlavy, roztrúsenou sklerózou, úrazmi miechy, dystóniou, prípadne inými ochoreniami a úrazmi nervového systému. NMDA receptory sú dôležité pre funkciu pamäti a schopnosť učiť sa [Rison a Stanton: Neurosci. Biobehav. Rev., 19 (1995), 533 - 552; Danysz et al: Behavioral. Pharmacol., 6 (1995), 455 - 474]. Znížená funkcia týchto receptorov vedie k symptómom schizo13 frénie [Olney a Farber: Archives General Psychiatry, 52 (1996), 998 - 1007]. Preto sa látky, ktoré inhibujú GlyT-1, a tým zvyšujú aktivitu NMDA receptorov, používajú ako moderné psychofarmaká na ovplyvnenie psychóz a demencie pri liečbe chorôb, pri ktorých dochádza k poruchám pozornosti a organickému ochoreniu mozgu. Naopak, zvýšená aktivity NMDA receptorov sa využíva pri liečbe radu chorôb, ktoré súvisia s odumieraním nervov, ku ktorým sa radí napríklad mŕtvica, úrazy hlavy, prípadne neurogeneratívne choroby, ako Alzheimerova choroba, demencia následkom infarktu alebo AIDS, Huntingtonova choroba, Parkinsonova choroba, amiotrofná laterálna skleróza a iné ochorenia, pri ktorých dochádza k odumieraniu nervových buniek [Coyle a Puttfarcken: Science, 262 (1993), 689 - 695; Lipton a Rosenberg; New Eng. J. of Medicíne, 330 (1993), 613 - 622; Choi: Neurón, 1 (1988), 623 - 634]. Je tedy možné povedat, že farmaká, ktoré zvyšujú aktivitu GlyT-1, a tým znižujú aktivitu NMDA receptorov, sa využívajú na liečbu uvedených chorôb. Zjednodušene povedané, ide o lieky bezprostredne blokujúce väzbu glycínu na NMDA receptoroch.Convulsive conditions that are treated by altering glycine receptors are associated with epilepsy, stroke, head trauma, multiple sclerosis, spinal cord trauma, dystonia, or other diseases and injuries of the nervous system. NMDA receptors are important for memory function and ability to learn [Rison and Stanton: Neurosci. Biobehav. Rev. 19 (1995), 533-552; Danysz et al., Behavioral. Pharmacol., 6 (1995), 455-474]. Decreased function of these receptors leads to symptoms of schizo13 thuringia [Olney and Farber: Archives General Psychiatry, 52 (1996), 998-1007]. Therefore, agents that inhibit GlyT-1 and thereby increase NMDA receptor activity are used as modern psychopharmaceuticals to affect psychoses and dementia in the treatment of diseases in which attention disorders and organic brain disease occur. Conversely, increased NMDA receptor activity is used in the treatment of a variety of diseases related to nerve death, such as stroke, head trauma, or neurogenerative diseases such as Alzheimer's disease, dementia due to heart attack or AIDS, Huntington's disease, Parkinson's disease, andmiotrophic lateral sclerosis and other diseases in which neuronal cell death occurs [Coyle and Puttfarcken: Science, 262 (1993), 689-695; Lipton and Rosenberg; New Eng. J. of Medicine, 330 (1993), 613-622; Choi: Neuron, 1 (1988), 623-634]. Thus, drugs that increase the activity of GlyT-1 and thereby reduce the activity of NMDA receptors are useful in the treatment of these diseases. Basically, they are drugs that immediately block glycine binding at NMDA receptors.

Podstata vvnálezuThe essence of the invention

Zlúčeniny vzorca (I), ktoré sú predmetom predkladaného vynálezu, sa vyskytujú popri vhodnom nosiči ako aktívna zložka radu farmaceutických kompozícií. Tie sa pripravujú dokonalým zmiešaním efektívneho množstva príslušnej zlúčeniny (I) vo forme kyslej alebo zásaditej adičnej soli (aktívna zložka) s vhodným nosičom zvoleným podía spôsobu aplikácie lieku (orálny, perkutánny, parenterálne injekcie). Na výrobu liekov pre orálnu aplikáciu slúžia bežné kvapalné farmaceutické médiá, ako sú voda, glykoly, oleje, alkoholy - výslednými produktmi sú v tomto prípade suspenzie, sirupy, elixíry a kvapky, alebo pevné nosiče, napríklad škrob, cukry, kaolín, mazivá, spojivá, rozmelnené látky, z ktorých sa potom pripravujú prášky, pilulky, kapsuly a tablety. Na orálnu aplikáciu sa najčastejšie používajú tablety a kapsuly. Parenterálne zmesi obsahujú prevážne vodu, ktorá sa prípadne doplní inou zložkou, napríklad podporujúcou rozpustnosť. Injekčné roztoky sa spravidla pripravujú ako solné roztoky, glukózové roztoky alebo ako ich zmes. V prípade, že tieto roztoky obsahujú zlúčeniny (I), pripravujú sa z dôvodu zvýšenia účinnosti aj v olejovitej forme. Na tento účel sa hodí napríklad píniový olej, sezamový olej, bavlníkový olej, obilný olej, sójový olej, syntetické estery glycerolu a vyšších mastných kyselín, prípadne zmesi týchto látok. Injekčné roztoky môžu mat tiež charakter suspenzie. Pri prípravkoch vhodných na perkutánnu aplikáciu nosič spravidla obsahuje namáčadlo, prípadne aj látku ulahčujúcu vstrebávanie, zvyčajne v zmesi s malým množstvom prírodnej látky, ktorá nemá škodlivý vplyv na kožu. Uvedené prísady napomáhajú dosiahnuť optimálne zloženie zmesi, a prípadne tiež ulahčujú podkožnú aplikáciu prípravku. Perkutánne (podkožné) zmesi sa aplikujú rôzne - formou náplastí, bodovo s velmi presnou lokalizáciou alebo ako masti. Na prípravu vodných roztokov sa zlúčeniny (I) používajú prevážne vo forme adičných solí, ktoré sú vo vode lepšie rozpustné ako zodpovedajúce volné bázy alebo kyseliny.The compounds of formula (I) of the present invention are present in addition to a suitable carrier as an active ingredient in a variety of pharmaceutical compositions. These are prepared by intimately mixing an effective amount of the respective compound (I) in the form of an acid or base addition salt (active ingredient) with a suitable carrier selected according to the route of administration (oral, percutaneous, parenteral injection). Oral pharmaceuticals are prepared by conventional liquid pharmaceutical media such as water, glycols, oils, alcohols - the resulting products are suspensions, syrups, elixirs and drops, or solid carriers such as starch, sugars, kaolin, lubricants, binders , comminuted substances from which powders, pills, capsules and tablets are then prepared. Tablets and capsules are most commonly used for oral administration. Parenteral compositions comprise predominantly water, optionally supplemented with another component, for example, to aid solubility. Injectable solutions are generally prepared as saline solutions, glucose solutions or mixtures thereof. When these solutions contain compounds (I), they are also formulated in oily form to enhance their effectiveness. Suitable for this purpose are, for example, pine oil, sesame oil, cottonseed oil, cereal oil, soybean oil, synthetic esters of glycerol and higher fatty acids, or mixtures thereof. Injectable solutions may also be a suspension. In formulations suitable for percutaneous administration, the carrier generally comprises a wetting agent, and optionally an absorbent, usually in admixture with a small amount of a natural substance that does not adversely affect the skin. Said additives help to achieve an optimum composition of the composition and possibly also facilitate subcutaneous application of the composition. Percutaneous (subcutaneous) mixtures are applied differently - in the form of patches, point-to-point with very precise localization or as ointments. For the preparation of aqueous solutions, the compounds (I) are used predominantly in the form of addition salts which are better soluble in water than the corresponding free bases or acids.

Pre jednoduchosť a jednotnosť opisu je výhodné uvádzať množstvá farmaceutických zmesí v dávkovacích jednotkách, pričom každá jednotka obsahuje vopred stanovené množstvo aktívnej zložky vyrátané na dosiahnutie požadovaného terapeutického efektu v spojení s vhodným farmaceutickým nosičom. Príklady takých jednotiek sú napríklad tablety (ako základné, tak poťahované), kapsuly, pilulky, vrecká prášku, oblátky, injekčné roztoky alebo suspenzie, čajová lyžica, polievková lyžica a iné, prípadne ich pomerné množstvo.For the sake of simplicity and consistency of the description, it is preferable to indicate the amounts of the pharmaceutical compositions in dosage units, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical carrier. Examples of such units are, for example, tablets (both base and coated), capsules, pills, powder sachets, cachets, injectable solutions or suspensions, teaspoon, tablespoon and others, or a proportional amount thereof.

Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION

Príklad A.lExample A.l

Zmes dimetyl (tetrahydro-3,3-difenyl-2-furylidén)amóniumbromidu (0,01 molu) pripraveného podlá patentu US 3,714,159, (+/-)-4-(11,12-dihydro-6tf-benzimidazo[2,1-b][3]benzazepin-6yl)-piperidínu (0,01 molu), Na2CO3 (0,01 molu) a KI (10 mg) v metyl izobutylketóne (200 ml) sa mieša protiprúdne cez noc. Rozpúšťadlo sa odparí a zvyšok sa rozpustí v zmesi voda/CH2Cl2· Organická vrstva sa oddelí a vodná vrstva sa opäť extrahuje zmesou voda/CH2Cl2· Obidva podiely organickej fázy sa vysušia, filtrujú a rozpúšťadlo sa odparí. Odparok sa potom prečistí na sklenenom filtri cez silikagél (eluentom je zmes CH2C12/CH3OH v pomere 95:5 až 90:10). Čisté frakcie sa zlúčia a nechajú odpariť. Odparok sa nechá kryštalizovať z CH3CN za vzniku 0,88 g (15 %) (+/-) -4- (11,12-dihydro-6/ŕ-benzimidazo[ 2, l-b] [ 3 ]benzazepin 6-yl)-N,N-dimetyl—α,α-difenyl-l-piperidínbutánamidu (zlúč. č. 1, bod topenia 255,3’C).A mixture of dimethyl (tetrahydro-3,3-diphenyl-2-furylidene) ammonium bromide (0.01 mol) prepared according to U.S. Pat. No. 3,714,159, (+/-) - 4- (11,12-dihydro-6H-benzimidazo [2,1-a]) -b] [3] Benzazepin-6-yl) -piperidine (0.01 mol), Na 2 CO 3 (0.01 mol) and KI (10 mg) in methyl isobutyl ketone (200 mL) were stirred countercurrent overnight. The solvent was evaporated and the residue was dissolved in water / CH 2 Cl 2 · The organic layer was separated and the aqueous layer was extracted again with water / CH 2 Cl 2 · Both portions of the organic phase were dried, filtered and the solvent was evaporated. The residue is then purified on a glass filter through silica gel (eluent: CH 2 Cl 2 / CH 3 OH 95: 5 to 90:10). The pure fractions were combined and evaporated. The residue was crystallized from CH 3 CN to give 0.88 g (15%) of (+/-) -4- (11,12-dihydro-6 H -benzoimidazo [2,1b] [3] benzazepin 6-yl 1-N, N-dimethyl-α, α-diphenyl-1-piperidinobutanamide (Compound No. 1, melting point 255.3 ° C).

Príklad A.2Example A.2

Do zmesi 4-(3-bróm-2-oxopropyl)-N,J\T-dimetyl-a,a-difenyl1-piperidinbutánamidmonohydrobromidu (13 g) v metanole (80 ml) sa za miešania pridá (2,6-dimetylfenyl)tiomočovina (4,1 g) pri 70’C. Miešanie pokračuje asi hodinu pri rovnakej teplote. Rozpúšťadlo sa odparí a zvyšok sa rozpustí vo vode. Prídavkom uhličitanu draselného sa upraví hodnota pH na 9 a zmes sa extrahuje etylacetátom. Organická fáza sa prečistí acidobazickou extrakciou, vysuší sa, sfiltruje a rozpúšťadlo sa odparí. Odparok sa nechá kryštalizovať z metanolu. Zrazenina sa po filtrácii premyje a vysuší za vzniku 6,2 g (52 %) 4-[[2-[[2,6dimetylf enyl) amino ] -4-tiazolyl ]metyl ] -N, W-dimetyl-α, a-difenyl-l-piperidínbutánamidu (zlúčenina č. 47, bod topenia 210,5’C).To a mixture of 4- (3-bromo-2-oxopropyl) -N, N, N-dimethyl-α, α-diphenyl-1-piperidinobutanamide monohydrobromide (13 g) in methanol (80 mL) was added (2,6-dimethylphenyl) with stirring. thiourea (4.1 g) at 70 ° C. Stirring is continued for about an hour at the same temperature. The solvent was evaporated and the residue was dissolved in water. The pH was adjusted to 9 by the addition of potassium carbonate and the mixture was extracted with ethyl acetate. The organic phase is purified by acid-base extraction, dried, filtered and the solvent is evaporated. The residue is crystallized from methanol. The precipitate was washed and dried to give 6.2 g (52%) of 4 - [[2 - [[2,6-dimethylphenyl) amino] -4-thiazolyl] methyl] -N, N-dimethyl-α, α- diphenyl-1-piperidine-butanamide (Compound No. 47, melting point 210.5 ° C).

Analogicky sa pripravujú:Similarly prepared:

4- [ [ 2- [ [ 2,6-dichlórf enyl)amino ] -4-tiazolyl ]metyl ] -N, AT-dimetyl α,α-difenyl-l-piperidínbutánamid (zlúč. č. 48, bod topenia 207,0-C) a4 - [[2 - [[2,6-dichlorophenyl) amino] -4-thiazolyl] methyl] - N, N -dimethyl α, α-diphenyl-1-piperidinobutanamide (comp. 48, melting point 207, 0-C) a

N,N-dimetyl-4- [ [ 2- (metylamino) -4-tiazolyl]metyl]-α, α-difenyl1-piperidínbutánamid (zlúčenina č. 49, bod topenia 188,3’C).N, N-dimethyl-4 - [[2- (methylamino) -4-thiazolyl] methyl] - α, α-diphenyl-1-piperidine-butanamide (Compound No. 49, melting point 188.3 ° C).

Príklad A.3Example A.3

Do zmesi NaH (0,55g, 78% disperze) v 1,4-dioxáne (50 ml) sa za miešania pridá l-(4-f luórfenyl)-AT, Ar-dimetyl-4-οχο—α, adifenyl-l,3,8-triazaspiro[4,5]-dekán-8-butánamid (7,7 g). Po hodine miešania pri laboratórnej teplote sa zmes zahreje na 60C pridá sa chlórmetylbenzén (2,3 g).Miešanie pokračuje cez noc pri 60“C. Potom sa reakčná zmes preleje do nádoby s vodou a extrahuje sa CHC13. Extrakt sa premyje vodou, vysuší, sfiltruje a rozpúšťadlo sa odparí. Odparok sa prečistí na chromatograf icke j kolóne cez silikagél, kde eluentom je zmes CHC13 a 3% metanolu sýtená plynným amoniakom. Čisté frakcie sa zlúčia, rozpúšťadlo sa odparí a odparok sa rozmelní v n-hexáne. Zrazenina sa odfiltruje a vysuší za vzniku 2 g l-(4-fluórfenyl ) -N, AT-dimetyl-4-οχο—α, a-dif enyl-3-f enylmetyl-1,3,8-triazaspiro[4,5]-dekán-8-butánamid (zlúčenina č. 50, bod topenia 139,8’C). Tabuíky 1 a 2 uvádzajú zlúčeniny pripravené podía príkladu A.I. Niektoré z týchto zlúčenín sa pripravili pri použití rozdielnej bázy alebo rozpúšťadla, prípadne bez prídavku KI. Reakčné podmienky uvedené v tabulke znamenajú: MIK je skratka pre metylizobutylketón, DMA predstavuje AT, AT-dimetylacetamid a DMF je JV,JV-dimetylformamid.To a mixture of NaH (0.55g, 78% dispersion) in 1,4-dioxane (50 mL) was added 1- (4-fluorophenyl) -AT, N-dimethyl-4-oxo-α, adiphenyl-1 with stirring. 3,8-triazaspiro [4.5] decane-8-butanamide (7.7 g). After stirring for one hour at room temperature, the mixture was warmed to 60 ° C and chloromethylbenzene (2.3 g) was added. Stirring was continued at 60 ° C overnight. The reaction mixture was poured into a container of water and extracted with CHC1 third The extract was washed with water, dried, filtered and the solvent was evaporated. The residue was purified on a chromatographic column over silica j, wherein the eluent is a mixture of CHC1 3 and 3% methanol saturated by ammonia gas. The pure fractions were combined, the solvent was evaporated and the residue was triturated in n-hexane. The precipitate was filtered off and dried to give 2 g of 1- (4-fluorophenyl) -N, N-dimethyl-4-oxo-α, α-diphenyl-3-phenylmethyl-1,3,8-triazaspiro [4,5] decan-8-butanamide (Compound No. 50, melting point 139.8 ° C). Tables 1 and 2 list the compounds prepared according to Example A1 Some of these compounds were prepared using a different base or solvent, optionally without the addition of KI. The reaction conditions in the table are as follows: MIK stands for methyl isobutyl ketone, DMA stands for AT, N-dimethylacetamide and DMF is N, N-dimethylformamide.

Podía príkladu A.I bez použitia KI sa tiež pripravili 1- (5-chloro-2-metylf enyl) -N, //-dimetyl-4-oxo-a, α-dif enyl-1,3,8 triazaspiro[4,5]-dekán-8-butánamid (zlúčenina č. 46, bod topenia 175,7’C).1- (5-chloro-2-methylphenyl) -N, N-dimethyl-4-oxo-α, α-diphenyl-1,3,8 triazaspiro [4,5] were also prepared according to Example A1 without the use of KI. decan-8-butanamide (Compound No. 46, melting point 175.7 ° C).

Farmakologické príkladyPharmacological examples

Príklad B.l Analýza transportu GlyT-1 prenášačmiExample B. I Analysis of GlyT-1 transport by transporters

Subkonfluentné HEK 293-GlyTl bunky (rad buniek, ktoré sú stabilným ľudským glycínovým prenášačom 1) sa naočkujú na Cytostar-T testovacie platne v koncentrácii 50 000 buniek na jednu jamku v 100 μΐ DMEM média (Dulbecco1s Modified Eagle Médium sýtené 10% fetálnym hovädzím sérom, lmM pyruvát sodný, 100 jednotiek U penicilínu/ml a 0,1 mg/ml streptomycínu). Bunky zreli 48 hodín pri 37‘C, 5 % C02 a 95% vlhkosti.Subconfluent HEK 293-GlyT1 cells (a series of cells that are stable human glycine transporter 1) are seeded on Cytostar-T test plates at a concentration of 50,000 cells per well in 100 μΐ DMEM medium (Dulbecco 1 with Modified Eagle Medium saturated with 10% fetal). bovine serum, 1 mM sodium pyruvate, 100 U units of penicillin / ml and 0.1 mg / ml streptomycin). The cells were aged at 37 ° C, 5% CO 2 and 95% humidity for 48 hours.

Tretí deň sa bunky premyli v práčke Tecan PW96 riadenej mikroprocesorom, ktorá je schopná preprat všetkých 96 jamiek jednej platne súčasne absorpčným tlmivým roztokom (25 mM Hepes, 5,4 mM glukonát draselný, 1,8 mM glukonát vápenatý,On the third day, the cells were washed in a microprocessor-controlled Tecan PW96 washer capable of washing all 96 wells of one plate simultaneously with absorption buffer (25 mM Hepes, 5.4 mM potassium gluconate, 1.8 mM calcium gluconate,

0,8 mM MgSO4, 140 mM NaCl, 5mM glukóza a 5 mM alanín, pH roztoku sa upravilo 2M Tris na 7,5). Tecan PW96 sa naprogramovala tak, aby prepierala bunky päťkrát, pričom do každej jamky dávkovala 75 μΐ roztoku. Testované látky sa rozpustili v mikromoloch DMSO s rôznou koncentráciou. Do každej jamky sa pridal 1 μΐ testovacieho roztoku a bunky sa nechali zrieť 5 až 10 minút pri laboratórnej teplote. Potom sa pridalo 25 μΐ 30 M [U14C] glycínu rozpusteného v absorpčnom tlmivom roztoku a bunky sa nechali zrieť pri laboratórnej teplote ešte hodinu Nakoniec sa platne uzatvorili a absorpcia [U14C] glycínu sa merala scintilačnou rúrou TopCount (Packard microplate scintillation counter). Z výsledkov získaných pre rôzne koncentrácie testovaných látok sa vyrátala práve taká koncentrácia, pri ktorej sa absorpcia glycínu inhibuje z 50 % (IC50). V tabuľke 3 sú zhrnuté koncentrácie vyrátané pre látky opísané v predkladanom vynáleze. Hodnota PIC50 vyjadruje záporný dekadický logaritmus IC50.0.8 mM MgSO 4 , 140 mM NaCl, 5 mM glucose and 5 mM alanine, the pH of the solution was adjusted to 7.5 with 2M Tris). Tecan PW96 was programmed to wash the cells five times, dispensing 75 μΐ of solution into each well. Test substances were dissolved in micromoles of DMSO at various concentrations. 1 μΐ of test solution was added to each well and the cells were aged for 5 to 10 minutes at room temperature. Then 25 μΐ 30 M [U 14 C] glycine dissolved in the absorption buffer was added and the cells were aged at room temperature for an hour. Finally, the plates were sealed and the [U 14 C] glycine uptake was measured by TopCount (Packard microplate scintillation counter scintillation tube). ). From the results obtained for various concentrations of test substances, the concentration at which glycine absorption is inhibited by 50% (IC 50 ) was calculated. Table 3 summarizes the concentrations calculated for the substances described in the present invention. The PIC 50 value represents the negative decimal logarithm of the IC 50 .

Tabuíka 1Table 1

Zlúč w c. Cmpd w c. Rs R s R4 R 4 Reakčné podmienky báza/KI/rozpúšťadlo Base / KI / solvent reaction conditions Fyzikálne vlastnosti bod topenia: b.t. v °C Physical properties melting point: m.p. ° C 8 8 H H Na2CO2/-/MIKNa 2 CO 2 / - / MIC b.t. 12^9*0, H2O (1:1)bt 12 ^ 9 * 0, H 2 O (1: 1) 9 9 |H=“O~F -<σοκ | H = “O ~ F - <σ οκ H H NajCOj / KJ / MIK NajCOj / KJ / MIC b.t. 184,5“C mp 184.5 "C 10 10 Px> P x> H H Na:CO,/Kl/MIKTo : CO, / KI / MIC b.t. 161,4eCmp 161.4 e C 11 11 OH OH Na2CO, t KÍ / MIKNa 2 CO, t KI / MIC b.t. 170,5eCmp 170.5 e C -ch'\X3- ch '\ X3 12 12 —CH, CH, OH OH Na:COj/Kl/NlIKTo : COj / Kl / NlIK b.t. 135-C mp 135-C 13 13 -ó- -about- El,N/-/DMA El N / - / DMA b.t. 16I,3eC;bt 16I, and C 3; o about HCI (1:1); H2O(1:1)HCl (1: 1); H 2 O (2: 1) 14 14 n -CH-C-CIb-CHt n CH-C-CI b-CHt A A H H Na2COj/-/MIKNa 2 CO 3 / - / MIC b.t. 160.7’C; mp 160.7'C; ô about šťavelan (3:2)  oxalate (3: 2) 15 15 -NH-/“) NH / ") H H NajCOj/KI/MIK NajCOj / KI / MIK b.t. 265/4’C; HBr(2:1) mp 265 / 4'c; HBr (2: 1) 16 16 H H Na2COj/-/MIKNa 2 CO 3 / - / MIC b.t. 139,1’C mp 139,1'C o about CMj-CH, CMJ-CH 17 17 H H NajCOj 7 Kl / MIK NajCOj 7 Kl / MIC b.t. 199,4’C mp 199,4'C 18 18 íl /=\ —c-wh-chXI clay / = \ c-wh-chXI -O -ABOUT Na2CO, / Kl / MIKFor 2 CO, / KI / MIC b.t. 111,5-145’C; mp 111,5-145'C; HjO(2:l) Hjo (2: l) 19 19 •^tO Ô • ^ tO ABOUT H H NasCO,/-/MlKNa with CO, / - / MlK b.t. 188,8’C mp 188,8'C

Zlúč Č.Pool No

R4 R 4

Reakčné podmienky báza/KI/rozpúšťadloBase / KI / solvent reaction conditions

Fyzikálne vlastnosti bod topenia: b.t. v °CPhysical properties melting point: m.p. ° C

o. f h, —C-NH-CH—4 ň —NH-C—about. f h, —C-NH-CH — 4 '—NH-C—

—NHNH

Na,CO, / ΚΙ / MIKNa, CO, ΚΙ / MIC

Na,CO,/-/MIKNa, CO / - / MIK

b.t. 111,9’C; HCI (2:1)mp 111,9'C; HCI (1: 1)

b.L 202-205’C —Nllb.L 202-205’C —Nll

UU

-CF, \^N-CF,

ci í C,,J /=\ci í C ,, J / = \

-N— Cll--N— Cll-

—ľn.-o-cii— —en,-Ľ—n—N.-o-cii— —en, - L —n

-CH,-í-NCH, -I, -N

OHOH

HH

IIII

Na,CO, / KI / DMFNa, CO, / KI / DMF

Na2C0, / KI / MIKAt 2 C0, / KI / MIK

Na,COj/KI/MlKHere, NAV / KI / MLK

NajCO,/-/MIKNajCO, / - / MIK

Na:C0i/-/MIKOn : C0i / - / MIK

Na,C0,/-/MIKHere, C0 / - / MIK

Na:C0,/-/MIKOn : C0, / - / MIC

NajCO, / KI / MIKNajCO, / KI / MIC

NaHC0,/-/DMFNaHC0, / - / DMF

b.t. 192,4’Cmp 192,4'C

b.t. 156, l’Cmp 156, l'C

b.t. 208,9’C (E)-2-fumarát (1:1)mp 208.9'C (E) -2-fumarate (1: 1)

b.t. 257,4’Cmp 257,4'C

b.t. 176,2’C;mp 176,2'C;

;E)-2-fumarát (1:1)E) -2-fumarate (1: 1)

b.t. 142,7’Cmp 142,7'C

b.t. 198,0’C; šťavelan (1:1)mp 198,0'C; oxalate (1: 1)

b.t. 133,1-135,l’C; šťavelan (2:5)mp 133.1 to 135 &apos;C; oxalate (2: 5)

b.t. 148,7’C; št’aveťan (1:2)mp 148,7'C; Stewart (1: 2)

b.t. 121,8’Cmp 121,8'C

HH

NaHC0,/-/DMFNaHC0, / - / DMF

Zlúč. č. Bile. no. R5 R 5 R4 R 4 32 32 H H 33 33 Cl ρ-θ-F CH, Cl ρ-θ-F CH, OH OH 34 34 CH, CH, H H 35 35 p-Q- OH p -Q- OH H H 36 36 í!_O~f -CO s! ~ _ O f CO H H 37 37 pO* -co n after* -what n OCH) OCH) 38 38 fV-0 Cl FV-0 Cl 011 011 39 39 _£Υφ CH, _ £ Υφ CH, OH OH 40 40 ~α,·ΌΟ~ α, ΌΟ H H 41 41 p~ô ^CO p-delta ^ CO H H

Reakčné podmienky báza/KI/rozpúšťadlo Base / KI / solvent reaction conditions Fyzikálne vlastnosti bod topenia: b.t. v °C Physical properties melting point: m.p. ° C NaHCO,/-/DMF NaHCO / - / DMF b.t. 251,O’C mp 251 O'C EtjN / t DMF Et 3 N / t DMF b.t. 183,3’C mp 183,3'C NaHCO,/-/DMF NaHCO / - / DMF b.t. 257,3’C mp 257,3'C EtjN / - / DMF Et 3 N / - / DMF b.t. 136,5’C; šťavclnn (1:3) mp 136,5'C; juicy (1: 3) Níi;CO, /-/DMF Ni, CO, - / DMF b.t. 207,4OC: i šťaveťan (1:2)bt 207.4 O C: i oxalate (1: 2) Na:COj/-/DMFNa : CO 3 / - / DMF b.t. 220, l’C; (E)-2· fumarát (1:1) mp 220, l'C; (E) -2 · fumarate (1: 1) NaHCOj/-/DMF NaHCO / - / DMF b.t. 183.7’C; HCI (2:1); etanol (1:1) mp 183.7'C; HCl (2: 1); ethanol (1: 1) NaHCOj/>/DMF NaHCO /> / DMF b.t. 198,7*C mp 198.7 ° C NajCOj/-/DMA NajCOj / - / DMA b.t. 183,9’C mp 183,9'C NajCOj/-/DMA NajCOj / - / DMA b.t. 201,4’C; (E)-2- fúmarát (2:3) mp 201,4'C; (E) -2-fumarate (2: 3)

Zlúč ¢. Cmpd ¢. R5 R 5 R4 R 4 Reakčné podmienky báza/KI/rozpúšťadlc The base / KI / solvent reaction conditions Fyzikálne vlastnosti bod topenia; b.t. v °C Physical properties melting point; mp ° C 42 42 -tCO -tCO H H Na,COj/-/DMF For, NAV / - / DMF b.t. 177,8’C; mp 177,8'C; CIIj CIIj (Z)-2- fumarat (1:2) (Z) -2- fumarate (1: 2) 43 43 -“*-0-0 - "* - 0-0 H H Na2COj / ΚΙ 1 DMFNa 2 CO 3 / ΚΙ 1 DMF b.t. 190,5‘C mp 190,5'C 53 53 p-O“F =a,-N<O í -N—C—CH,pO ' F = a, - N <O - - - C - CH, OH OH Na2CO,/-/MlKNa 2 CO, / - / MlK b. t. 164,5‘C b. t. 164,5'C 54 54 •CHj-O-CHj • CH-O-CH Na,COj/-/M!K For, NAV / - / M? K b.t. 155,4’C; HCI (1:1) mp 155,4'C; HCI (2: 1) rs rs

Tabuľka 2Table 2

Zlúč. č. Bile. no. R3 R 3 Reakčné podmienky báza/KI/rozpúšťadlo Base / KI / solvent reaction conditions Fyzikálne vlastnosti bod topenia: b.t. v °C Physical properties melting point: m.p. ° C 44 44 NajCOj / ΚΙ / MIK NajCOj / ΚΙ / MIC b.t. 206,6’C; (E)-2-fúmarát (1:1) mp 206,6'C; (E) -2-fumarate (1: 1) 45 45 crto ortho position Na,COj / ΚΪ / MIK Na, COj / ΚΪ / MIC b.t. 174/5“Cmp 174/5 "C

Tabulka 3Table 3

Zlúč. w c. Bile. w c. PICso PICS Zlúč. v c. Bile. in c. PICso PICS 1 1 7,28 7.28 28 28 6,56 6.56 2 2 6,80 6.80 29 29 6,10 6.10 3 3 6,77 6.77 30 30 6,63 6.63 4 4 6,49 6.49 31 31 6,17 6.17 5 5 6,43 6.43 32 32 6,12 6,12 6 6 6,17 6.17 33 33 6,21 6.21 7 7 6,16 6.16 34 34 6,35 6.35 8 8 6,05 6.05 35 35 6,22 6.22 9 9 6,13 6.13 36 36 6,25 6.25 10 10 6,62 6.62 37 37 6,90 6.90 11 11 6,89 6.89 38 38 6,04 6.04 12 12 6,15 6.15 39 39 6,23 6.23 13 13 6,28 6.28 40 40 6,36 6.36 14 14 6,03 6.03 41 41 6,52 6.52 15 15 6,04 6.04 42 42 6,12 6,12 16 16 6,12 6,12 43 43 6,12 6,12 17 17 6,13 6.13 44 44 6,70 6.70 18 18 6,03 6.03 45 45 6,00 6.00 19 19 6,29 6.29 46 46 6,27 6.27 20 20 6,39 6.39 47 47 6,79 6.79 21 21 6,08 6.08 48 48 6,54 6.54 22 22 6,03 6.03 49 49 6,12 6,12 23 23 6,03 6.03 50 50 6,60 6.60 24 24 6,08 6.08 51 51 6,91 6.91 25 25 6,36 6.36 52 52 6,47 6.47 26 26 6,10 6.10 53 53 6,39 6.39 27 27 6,26 6.26 54 54 6,61 6.61

Testovali sa takisto zlúčenina 51, čo je 4 - [ [ 1- (f luorfenyl) metyl ] -l/ŕ-benzimidazol-2-yl ] metyl ] -N, Ndimety1-a,α-difenyl-l-piperidínbutánamid, pripravený podlá patentu US 4,695,575 a zlúčenina 52, ktorou jeCompound 51, which is 4 - [[1- (fluorophenyl) methyl] -1H-benzimidazol-2-yl] methyl] -N, N-dimethyl-α, α-diphenyl-1-piperidinobutanamide, prepared according to No. 4,695,575 and Compound 52 which is

4- [ [ 9-1 (4-metoxyf enyl) metyl ] -9/í-purin-8-yl ] amino ] -N, Ndimetyl-α,a-difenyl-l-piperidínbutánamid (E)-2-buténdioát (2:5), pripravený podlá patentu US 5,008,268.4 - [[9-1 (4-Methoxyphenyl) methyl] -9H-purin-8-yl] amino] -N, N-dimethyl-α, α-diphenyl-1-piperidinobutanamide (E) -2-butenedioate ( 2: 5), prepared according to U.S. Patent No. 5,008,268.

Príklady zloženiaComposition examples

Nasledujúci príklad charakterizuje typické zloženie farmaceutickej látky vhodnej na pravidelné podávanie zvieratám a luďom. Účinná zložka (A.I.) predstavuje zlúčeninu (I) alebo na farmaceutické účely vhodnejšiu adičnú sol príslušnej zlúčeniny.The following example characterizes a typical pharmaceutical composition suitable for regular administration to animals and humans. The active ingredient (A.I.) represents compound (I) or a more suitable addition salt of the compound for pharmaceutical purposes.

Príklad 1 Poťahované tabletyExample 1 Coated tablets

Príprava základnej tabletyPreparation of the base tablet

Zmes 100 g A.I., 570 g laktózy a 200 g škrobu sa dobre premiesi a zvlhčí roztokom 5 g dodecylsulfátu sodného a 10 g polyvinylpyrolidónu v asi 200 ml vody. Zmes vlhkého prášku sa prešeje, vysuší a opäť prešeje. Potom sa pridá 100 g mikrokryštalickej celulózy a 15 g hydrogenovaného rastlinného oleja. Celá zmes sa dobre premieša a zlisuje do tabliet; z uvedeného množstva sa pripraví 10 000 tabliet, každá obsahuje 10 mg účinnej zložky.A mixture of 100 g of A.I., 570 g of lactose and 200 g of starch is mixed well and moistened with a solution of 5 g of sodium dodecyl sulfate and 10 g of polyvinylpyrrolidone in about 200 ml of water. The wet powder mixture is sieved, dried and sieved again. 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil are then added. The whole mixture is mixed well and compressed into tablets; from this amount, 10,000 tablets are prepared, each containing 10 mg of the active ingredient.

Poťahovaniecoating

Do roztoku 10 g metylcelulózy v 75 ml denaturovaného etanolu sa pridá roztok 5 g etylcelulózy v 150 ml dichlórmetánu. Potom sa pridá ešte 75 ml dichlórmetánu a 2,5 ml 1,2,3-propántriolu. Popri tom sa 10 g polyetylénglykolu roztopí a rozpustí v 75 ml dichlórmetánu. Prvý a druhý roztok sa zmieša, pridá sa 2,5 g oktadekanoátu horečnatého, 5 g polyvinylpyrolidónu a 30 ml koncentrovanej farebnej suspenzie. Všetko sa zhomogenizuje. Základné tablety sa potiahnu takto získanou zmesou v zodpovedajúcej aparatúre.To a solution of 10 g of methylcellulose in 75 ml of denatured ethanol is added a solution of 5 g of ethylcellulose in 150 ml of dichloromethane. Then 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol are added. In addition, 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The first and second solutions are mixed, 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated color suspension are added. Everything is homogenized. The base tablets are coated with the mixture thus obtained in the corresponding apparatus.

Claims (10)

PATENTOVÉ NÁROKYPATENT CLAIMS 1. Inhibítor prenosu glycínu využiteľný na prípravu lieku 'pre liečbu porúch centrálneho a periférneho nervového systému, * vyznačujúci sa tým, že má vzorec chemicky stereoizomér A-oxidu alebo farmaceutický adičná soľ, kdeA glycine transfer inhibitor useful in the preparation of a medicament for the treatment of central and peripheral nervous system disorders, characterized in that it has the formula chemically stereoisomer A-oxide or a pharmaceutical addition salt, wherein: R1 a R2 nezávisle od seba predstavujú vodíky alebo alkyly Cj až C4;R 1 and R 2 independently represent hydrogen or C 1 -C 4 alkyl; X predstavuje substituent vzorca r3 (a) (b)X represents a substituent of formula r 3 (a) (b) Z R5 kde čiarkovaná čara predstavuje ľubovoľnú väzbu;ZR 5 wherein the dotted line represents any bond; •j • predstavuje substituent vzorca (a-1) v ktorom každý zo substituentov R6 a R7 je vodík alebo sa obidva dohromady spoja s dvoma atómami uhlíka za vzniku fenylu?• j • represents a substituent of formula (a-1) wherein each of R 6 and R 7 is hydrogen or both together combine with two carbon atoms to form phenyl? R8 predstavuje vodík alebo halogén;R 8 represents hydrogen or halogen; n je 1 alebo 2;n is 1 or 2; R4 predstavuje vodík, hydroxyskupinu, Cj_4 alkyloxyskupinu Cj_4 alkyloxy C1_4 alkyl alebo aryl ^ι_4 alkyloxyskupinu? R5 predstavuje diarylmetyloxy C1-4 alkyl alebo substituent vzorca kde B1 predstavuje -CH2, -CH(OH)-, -NH-, -CH2-NH- alebo priamu väzbu;R 4 is hydrogen, hydroxy, C 1-4 alkyloxy C 1-4 alkyloxy C 1-4 alkyl or arylC 1-4 alkyloxy; R 5 represents diarylmethyloxy C 1-4 alkyl or a substituent of the formula wherein B 1 represents -CH 2 , -CH (OH) -, -NH-, -CH 2 -NH- or a direct bond; B2 predstavuje -NH-, -CH2- alebo priamu väzbu B3 predstavuje -NR12-, -CH2-, -C(=0)- alebo priamu väzbu B7 predstavuje -Ci_4 alkándiyl-NH- alebo -NH-C1_4 alkyl-;B 2 represents -NH-, -CH 2 - or a direct bond B 3 represents -NR 12 -, -CH 2 -, -C (= O) - or a direct bond B 7 represents - C 1-4 alkanediyl-NH- or -NH-C 1 _ 4 alkyl; B8 predstavuje -NR19-, -CH2- alebo -CH(aryl)-;B 8 is -NR 19 -, -CH 2 -, or -CH (aryl) -; Y predstavuje vždy nezávisle od seba atóm 0 alebo S; -a1=a2-a3=a4- predstavuje dvojväzný substituent vzorcaY is independently O or S; -a 1 = a 2 -a 3 = a 4 - represents a divalent substituent of the formula -CH=CH-CH=CH- (b-l-a) alebo-CH = CH-CH = CH- (b-1-a) or -N=CH-N=CH- (b-l-b);-N = CH-N = CH- (b-1-b); pričom vodíkový atóm v radikále (b-l-a) môže byť nahradený hydroxyskupinou;wherein the hydrogen atom in the radical (b-1-a) may be replaced by a hydroxy group; R9 predstavuje C1-4 alkyl, alebo C1-4 alkyl substituovaný arylom, tienylom, furanylom, furanylom substituovaným hydroxy C1-4 alkylom alebo tiazolylom;R 9 is C 1-4 alkyl, or C 1-4 alkyl substituted with aryl, thienyl, furanyl, furanyl substituted with hydroxy C 1-4 alkyl or thiazolyl; 1 n1 n RA predstavuje aryl, arylaminoderivat, cl-4 alkylaminoderivát, C1-4 alkyltioderivát;R A is aryl, arylamino, C l-4 alkylaminoderivát, C 1-4 alkylthio derivative; R11 predstavuje vodík, C1-4 alkyl, halogén- alebo trifluórmetyl;R 11 represents hydrogen, C 1-4 alkyl, halogen- or trifluoromethyl; R12 predstavuje vodík alebo 0χ_4 alkylkarbonyl;R 12 is hydrogen or χ 0 _ 4 alkylcarbonyl; R13 predstavuje vodík, C1_4 alkyl alebo aryl;R 13 is hydrogen, C 1 _ 4 alkyl or aryl; R14 predstavuje vodík alebo halogénderivát;R 14 represents hydrogen or a halogen derivative; R15 a R16 nezávisle od seba predstavujú vodík alebo aryl;R 15 and R 16 independently represent hydrogen or aryl; R17 predstavuje vodík alebo C1-4 alkyl;R 17 represents hydrogen or C 1-4 alkyl; R18 predstavuje aryl,R 18 represents aryl, 5/í-dibenz [ b, f ]azepin-5-yl alebo Cj_4 alkyl νοϊηβ substituovaný jedným alebo dvoma od seba nezávislými substituentmi tvorenými C3_7 cykloalkylom alebo arylom; R19 predstavuje vodík, Cj_4 alkylkarbonyl alebo diaryl <Α_4 alkyl;5 / s-dibenz [b, f] azepin-5-yl or 4 Cj_ νοϊηβ alkyl substituted with one or two substituents each independently formed by C 3 _ 7 cycloalkyl or aryl; R 19 represents hydrogen, C 1-4 alkylcarbonyl or diarylC 1-4 alkyl; R20, R21, R22 a R23 nezávisle od seba predstavujú vodík, cl-4 alebo aryl;R 20 , R 21 , R 22 and R 23 independently represent hydrogen, C 1-4 or aryl; R24 predstavuje vodík alebo trif luormetyl;R 24 represents hydrogen or trifluoromethyl; R25 predstavuje vodík alebo halogén; a v prípade, že radikál R5 má vzorec (b-3), môže R4 byt tiež fenyl ci_4 alkylaminokarbonyl; aR 25 represents hydrogen or halogen; and when the radical R 5 has the formula (b-3), R 4 can also be phenyl C 1-4 alkylaminocarbonyl; and R4 a R5 môžu spoločne vytvoriť spiroradikál vzorca kde R26 a R27 nezávisle od seba predstavujú vodík, C1-4 alkyl, aryl alebo aryl C1_4alkyl;R 4 and R 5 can together form a spiro radical of formula wherein R 26 and R 27 independently of one another hydrogen, C 1-4 alkyl, aryl or aryl C 1 _ 4 alkyl; aryl je v tomto prípade fenyl alebo fenyl substituovaný jedným alebo dvoma substituentmi nezávisle od seba tvorenými C^_4 alkylom, halogénderivátom, hydroxyskupinou a C1-4 alkyloxylom.aryl in this case is phenyl or phenyl substituted with one to two substituents independently of one another, formed by C ^ _ 4 alkyl, halide derivative, hydroxy, and C 1-4 alkyloxy. 2. Zlúčenina podlá nároku 1,vyznačujúca sa tým, že R1 a R2 sú metylové skupiny.Compound according to claim 1, characterized in that R 1 and R 2 are methyl groups. 3. Zlúčenina podlá nároku 1 alebo 2, vyznačuj úca sa t ý m, že X je radikál vzorca (a) alebo (b).A compound according to claim 1 or 2, wherein X is a radical of formula (a) or (b). 4. Využitie podlá nároku 1, vyznačujúce sa tým, že poruchou je psychóza, bolestivé stavy, epilepsia, neurodegeneratívne choroby, mozgová príhoda, úraz hlavy alebo roztrúsená skleróza.Use according to claim 1, characterized in that the disorder is psychosis, pain conditions, epilepsy, neurodegenerative diseases, stroke, head trauma or multiple sclerosis. 5. Zlúčenina podía jedného z nárokov laž3,vyzna• čujúcasatým, že keď sú vo vzorci (I) R4 vodík a R5 radikál vzorca (b—1), kde B1 je -CH2- a R9 je 4-fluórbenzyl, * potom -a1=a2-a3=a4- je iný ako -CH=CH-CH=CH-;A compound according to any one of claims 1 to 3, wherein, in formula (I), R 4 is hydrogen and R 5 is a radical of formula (b-1), wherein B 1 is -CH 2 - and R 9 is 4-fluorobenzyl * then -a 1 = a 2 -a 3 = a 4 - is other than -CH = CH-CH = CH-; a ďalej sa vyznačujúca tým, že keď sú R4 vodík a R5 radikál vzorca (b-1), kde B1 je -NH- a R9 je 4-metoxybenzyl, potom -a^=a2-a3=a4- je iný ako -CH=N-CH=N-.and further characterized in that when R 4 is hydrogen and R 5 is a radical of formula (b-1), wherein B 1 is -NH- and R 9 is 4-methoxybenzyl, then -a ^ = and 2 -a 3 = a 4 - is other than -CH = N-CH = N-. 6. Zlúčenina podía nároku 5,vyznačujúca sa tým, že R5 je diarylmetyloxy C1-4 alkyl alebo radikál vzorca (b-2), (b-3), (b-4), (b-5), (b-6), (b-7), (b-8), (b-9), (b-10), (b-11), (b-12) alebo (b-13); prípadne R5 môže vytvoriť spoločne s R4 spiroradikál vzorca (b-14).A compound according to claim 5, wherein R 5 is a diarylmethyloxy C 1-4 alkyl or a radical of formula (b-2), (b-3), (b-4), (b-5), (b -6), (b-7), (b-8), (b-9), (b-10), (b-11), (b-12), or (b-13); optionally R 5 can form together with R 4 a spiroradical of formula (b-14). 7. Spôsob využitia zlúčeniny podía nároku 5 alebo 6, vyznačujúci sa tým, že sa farmaceutická zmes skladá z terapeuticky efektívneho množstva účinnej zložky opísanej zlúčeniny a vhodného nosiča.The method of use of a compound according to claim 5 or 6, wherein the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient of the disclosed compound and a suitable carrier. 8. Spôsob podía nároku 7, vyznačujúci sa tým, že sa farmaceutická zmes pripraví dokonalým zmiesením terapeuticky efektívneho množstva zlúčeniny podía nároku 5 alebo 6 a vhodného farmaucetického nosiča.The method of claim 7, wherein the pharmaceutical composition is prepared by intimately mixing a therapeutically effective amount of a compound of claim 5 or 6 and a suitable pharmaceutical carrier. »» 9. Spôsob využitia zlúčeniny podía nárokov 5 a 6, vyznačujúci sa tým, že opísaná zlúčenina sa 11 použije ako liek.9. A method of using a compound according to claims 5 and 6, characterized in that the compound described is 11 used as a medicament. 10. Spôsob využitia zlúčeniny podía nároku 5, vyznačujúci sa tým, že pri príprave opísanej zlúčeniny reaguje medziprodukt vzorca (II), kde W” je zodpovedajúci náboj iónu alebo funkčného derivátu, s medziproduktom vzorca (III) v inertnom rozpúšťadle, v prítomnosti vhodnej bázy a jodidu draselného;A process for the use of a compound according to claim 5, wherein in the preparation of the described compound, an intermediate of formula (II) wherein W 'is a corresponding ion or functional derivative charge is reacted with the intermediate of formula (III) in an inert solvent in the presence of a suitable base. and potassium iodide; a kedf je to potrebné, premení sa zlúčenina vzorca (I) na kyslú adičnú sol reakciou s kyselinou, prípadne na zásaditú adičnú sol reakciou s bázou, alebo naopak kyslá adičná sol sa premení na volnú bázu reakciou so zásadou alebo zásaditá adičná sol na volnú kyselinu reakciou s kyselinou;and if desired, the compound of formula (I) is converted into an acid addition salt by reaction with an acid, optionally into a base addition salt by reaction with a base, or conversely, the acid addition salt is converted into a free base by reaction with a base or basic addition salt into a free acid by reaction with an acid; podlá požiadavky sa pripraví A-oxid a/alebo jeho stereoizoméryA-oxide and / or stereoisomers thereof are prepared as desired 01-1506-00-Če01-1506-00-CE
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