UA113876C2 - CARBAMATE / UREA DERIVATIVES - Google Patents

Abstract

The present invention relates to compounds of formula (I) (I) or salts thereof, wherein the substituents take the values indicated in the description; their preparation, their use as medicaments and medicines containing them.

Description

or their salts, where the substituents take the values specified in the description; their production, their use as medicinal products and medicinal products containing them. (Kg ra A o (or M o D

As X, r i )t

VO

The present invention relates to carbamate/urea derivatives, to their solid forms, to their preparation, to their use as medicinal products and to medicinal products containing them.

Y. Carbamate/urea derivatives

Histamine is a multifunctional chemical mediator that transmits signals through specific C-protein-coupled cell surface receptors (CSRs). To date, four subtypes of histamine receptors have been identified: NO, H2, НЗ and НИ. The НЗ receptor is a presynaptic SRSC, which is found predominantly in the central nervous system, although low levels are also found in the peripheral nervous system.Genes encoding NH receptors have been reported to be found in various organisms, including humans, and alternative splicing of these genes appears to result in The NZ receptor is an auto- and heteroreceptor, the activation of which leads to a decrease in the release of neurotransmitters (including histamine, acetylcholine, norepinephrine, dopamine and glutamate) from brain neurons and participates in the regulation of processes such as sleep and wakefulness, nutrition and memory In central nervous system systems, the receptor can be constitutively active.

Antagonists of the NZ receptor increase the release of cerebral histamine and other neurotransmitters, which in turn cause prolonged wakefulness, improvement of cognitive processes, reduction of food consumption and normalization of vestibular reflexes. Antagonists of the NZ receptor are disclosed, for example, in I algemu5Ka apa Kies-Kopopom/isg, Ekhrep Orip Tneg Raiepiv, 2010, 20(9), 1147-1169; Vaidaai" ei ai, Sitepi Toris5 ip Medisipai Spetivigu, 2010, 10, 153-169;

MO2007052124; MMO2007016496 and MMO2004101546.

Since the metabolic pathways of histamine are involved in a wide range of disorders, in particular, sleep disorders and wakefulness with excessive daytime sleepiness, for example, narcolepsy, it is believed that NZ receptor antagonists can be used in the pharmacotherapy of these disorders.

There is a need to develop new NZ receptor antagonists that would be good drug candidates. In particular, preferred compounds should efficiently bind to NH receptors, while exhibiting low affinity for other receptors, for example, receptors that mediate significant side effects, such as PEX tubules, which can cause side effects in relation to the cardiovascular system. They must be well absorbed from the gastrointestinal tract, be sufficiently metabolically stable, have favorable pharmacokinetic properties, be sufficiently absorbed by the brain, have a rapid onset of action, and be sufficiently long-lasting.

For example, in the treatment of narcolepsy, the pharmacokinetic properties of the compounds should lead to better wakefulness during the day, but at the same time lead to a minimal effect on nighttime sleep. Drug candidates must be non-toxic and exhibit few side effects. Furthermore, ideal drug candidates must be able to exist in a physical form that is stable, non-hygroscopic, and easy to formulate.

The compounds of this invention are NZ receptor antagonists and therefore potentially useful in the treatment of a wide range of disorders, especially narcolepsy.

In the first aspect, the present invention relates to the compound of formula I (Kg tA

Pov x; ? (0, or to its salt, where

B: represents C1-alkyl, C1-alkyl, C1-alkynyl, C3-cycloalkyl, C3-cycloalkenyl or C3-cycloalkyl-C:-alkyl; where the specified C:-alkyl, Sovalkenyl, Sgovalkynyl or C3cycloalkyl-C:-4alkyl may be substituted by one or more of the halogens; and where C3-cycloalkyl or C5 are indicated. vcycloalkenyl can be substituted by one or more of halogens, C:-alkyls or C-4haloalkyls; t is 1 or 2; n represents 0, 1, 2, C or 4; each Co independently represents halogen, hydroxyl, amino group, cyano group, nitro group, C-alkyl, C:-vehaloalkyl, C:-hydroxyalkyl, C:1-lalkoxy-C:-alkyl, amino-C:-alkyl, C :-4-alkyl-amino-

Sivalkyl, di(C:-alkyl)amino-Ci-alkyl, Sivalkoxy group, Sihaloalkyloxy group, C-

alkylamino group, di(C:-alkyl)amino group, Sgvalkenyl, Cg-haloalkenyl, Sgvalkynyl or C». halogenalkynyl; or C3-cycloalkyl, where one carbon atom can be replaced by an oxygen atom, where said C3-cycloalkyl can be attached to methylene directly or through C3-alkylene, and where C3-cycloalkyl can be substituted by one or more halogens; or two K2 near the same carbon atom together with the specified carbon atom form C3cycloalkyl;

Xy represents oxygen or -M(Na4)-;

Ba represents hydrogen, C3-alkyl, C3-cycloalkyl or C3-cycloalkyl-C: -alkyl, p represents 1, and d represents 1; p represents 0, and d represents 1; or p represents 0, and d represents 0; r is 0, 1, 2, C or 4; each Kz independently represents halogen, hydroxyl, amino group, cyano group, nitro group, C:alkyl, C:-vehaloalkyl, C:1-hydroxyalkyl, C:1-lalkoxy-C:-alkyl, amino-C:-alkyl, C :-4-alkyl-amino-

Sialkyl, di(C:-alkyl)amino-Ci-alkyl, Sialkyloxy group, Sihaloalkyloxy group, C-alkylamino group, di(C:-alkyl)amino group, Sgvalkenyl, Cg-haloalkenyl, Sgvalkynyl or C». halogenalkynyl; or C3-cycloalkyl, where one carbon atom may be replaced by an oxygen atom, where C3-cycloalkyl may be attached to methylene directly or through C:halkylene, and where C3-cycloalkyl may be substituted by one or more halogens; or two Kz near the same carbon atom together with the specified carbon atom form C3-vcycloalkyl;

A is a ke

M

7 t

Ivo, , where the bond marked with an asterisk is attached to the nitrogen atom;

Bo represents hydrogen, C:-alkyl, C 10 -alkenyl, C 1 -alkynyl, C 3 -cycloalkyl, C 5 -cycloalkenyl or C 3 -cycloalkyl-C 4 -alkyl; where C:-alkyl, subalkenyl, C 1-6 alkynyl or C 3-6 cycloalkyl-

C:-"alkyl can be substituted by one or more of halogens, hydroxyls or C:-alkoxy groups; and where said C3-cycloalkyl or C5-cycloalkenyl can be substituted by one or more of halogens, C1-4 alkyls or C1-4 haloalkyls;

Xg is nitrogen or carbon; 5 represents 0, 1, 2 or 3; each C is independently halogen, hydroxyl, amino group, cyano group, nitro group, C 1 -alkyl, C 1 -haloalkyl, C 1 -C 6 -hydroxyalkyl, C 1 -C 4 -alkyl C 1 -C 4 -alkyl, amino -C 1 -C 4 -alkyl C 4 -C 4 -alkyl -amino-

Sialkyl, di(C:-alkyl)amino-Ci-alkyl, Sialkyloxy group, Sihaloalkyloxy group, C-alkylamino group, di(C:-alkyl)amino group, Sgvalkenyl, Cg-haloalkenyl, Sgvalkynyl or C». halogenalkynyl; or C3-cycloalkyl, where one carbon atom can be replaced by an oxygen atom, where said C3-cycloalkyl can be attached to methylene directly or through C3-alkylene, and where said C3-cycloalkyl can be substituted by one or more halogens.

Unless otherwise indicated, the term "compounds of this invention" refers to compounds of formula (I) and their subformulas (for example, compounds of formula (I1-1)); to their prodrugs; solid forms of free forms or to salts of the specified compounds, for example, solid forms of this invention, and/or to prodrugs; hydrates or solvates of the specified compounds, their salts and/or prodrugs; as well as to all stereoisomers (including diastereoisomers and enantiomers), tautomers and isotopically labeled compounds (including deuterium substitution); as well as to naturally occurring fragments (eg polymorphs, solvates and/or hydrates).

Unless otherwise indicated, the terms used in the present specification have the following meanings: "Alkyl" represents a straight or branched alkyl group and may, for example, be methyl, ethyl, n- or isopropyl, n-, iso-, sec- or tert-butyl, n-pentyl, n-hexyl; C1-alkyl is preferably unbranched or branched C-alkyl, and methyl, ethyl, n-propyl, iso-propyl and tert-butyl are particularly preferred.

Each alkyl part of "alkoxy", "haloalkyl", etc. should have the values given for the above definitions for "alkyl", especially with respect to linearity and preferred size. "Szecycloalkyl" is a saturated alicyclic fragment containing from three to six carbon atoms. The term refers to such groups as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

A substituent that is substituted "one or more times", for example, as defined in the CC ratio, is preferably substituted with one to three substituents.

Halogen is usually fluorine, chlorine, bromine or iodine; preferably fluorine, chlorine or bromine.

Haloalkyl groups mainly have a long chain of 1-4 carbon atoms and are, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-rifluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1 ,1-difluoro-2,2,2-trichloroethyl, 2,2,2-trichloroethyl, 1,1,2,2-tetrafluoroethyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3 -pentafluoropropyl or 2,2,3,4,4,4-hexafluorobutyl.

In those cases where Xo is a carbon, said carbon may be unsubstituted, may be substituted by Ke, or may be used to attach A to the nitrogen of an adjacent piperidine/pyrrolidine/azetidine moiety.

Compounds of formula I can exist in an optically active form or in the form of mixtures of optical isomers, for example, in the form of racemic mixtures or diastereoisomeric mixtures. In particular, asymmetric carbon atom(s) may be present in compounds of formula I and their salts.

Unless otherwise stated in the description, all optical isomers and mixtures thereof, including racemic mixtures, are included in the present invention.

As used herein, the term "isomers" refers to different compounds that have the same molecular formula but differ in the arrangement and configuration of atoms. Also, as used herein, the term "optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a particular compound of the present invention, and includes geometric isomers. It should be understood that the substituent can be attached to the chiral center of the carbon atom. The term "chiral" refers to molecules that do not have the property of compatibility when their mirror images are superimposed, while the term "achiral" refers to molecules in which their mirror images overlap. Therefore, the present invention includes enantiomers, diastereoisomers or racemic compounds. "Enantiomers" are pairs of stereoisomers that are not mirror images of each other and are compatible. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used when necessary to denote a racemic mixture. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other. The absolute stereochemistry is determined according to the Kahn-Ingold-Prelog K-5 system. If the compound is a pure enantiomer, the stereochemistry at each chiral carbon can be defined as either K or 5. Separated compounds whose absolute configuration is unknown can be denoted as (83) or (-y depending on the direction (right- or left-handed) in which they rotate the plane of polarization of light at wavelength O of the sodium line.The compounds disclosed herein may contain one or more of the asymmetric centers and therefore may have enantiomers, diastereoisomers, and other stereoisomeric forms that can be separated in terms of absolute stereochemistry as (K)- or ( 5)-. Unless otherwise stated, the present invention is intended to include all possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. The optically active (K)- and (5)- isomers can be prepared using chiral synthons or chiral reagents, or separate using conventional techniques.

If the compound contains a double bond, the substituent can exist in the E or 2 configuration.

If the compound contains a disubstituted cycloalkyl, such cycloalkyl substituent may exist in the cis- or trans-configuration.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention may be in a racemic or enantiomerically enriched, for example, (K)-, (5)-, or (B, 5)- configuration. In some in variants, each asymmetric atom has at least 50 95 enantiomeric excess, at least 6095 enantiomeric excess, at least 70 95 enantiomeric excess, at least 8095 enantiomeric excess, at least 90 95 enantiomeric excess, at least 95 95 enantiomeric excess, or at least 99 95 enantiomeric excess (K) in or (5)- configurations. Substituents at atoms with unsaturated bonds can, if possible, be present in cis- (7) - or trans- (E)- form.

Accordingly, as used herein, a compound of this invention may be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof,

for example, in the form of practically pure geometric (cis or trans) isomers, diastereoisomers, optical isomers (antipodes), racemates or their mixtures.

Any resulting mixtures of isomers can be separated using the physicochemical differences of the constituents into pure or practically pure geometric or optical isomers, diastereoisomers, racemates, for example, by chromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can be separated into optical antipodes by known methods, for example, by resolving their diastereoisomeric salts obtained with optically active acids or bases and isolating the optically active acidic or basic compounds. In particular, the basic fragments can be used to separate the compounds of this invention into their optical antipodes, for example, by fractional crystallization of salts formed with optically active acids, for example, tartaric acid, dibenzoyltartaric acid, diadetyltartaric acid, di-O,O'-p-toluenetartaric acid acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be separated using chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.

Depending on the definition of the substituents, compounds of formula I can exist in various tautomeric forms. All tautomeric forms of compounds of formula I are included in the scope of this invention.

As used herein, the terms "salt" or "salts" refer to addition salts of acids or addition salts of bases corresponding to a compound, for example, a compound of this invention or a compound of formula 1I-14. "Salts" include, but are not limited to, "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of this invention and are not biologically or otherwise undesirable. The compounds of this invention may be able to form acidic and/or basic salts due to the presence of amino and/or carboxyl groups or similar groups.

Pharmaceutically acceptable acid addition salts can be prepared with inorganic acids and with organic acids, for example salts such as acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate,

Zo chloride/hydrochloride, chlorotheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate , nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrophosphate/dihydrophosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.

Inorganic acids with which salts can be formed include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids with which salts can be obtained include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, malic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, etc. Pharmaceutically acceptable base addition salts can be obtained with inorganic and organic bases.

Inorganic bases with which salts can be obtained include, for example, ammonium salts and salts of metals of groups I-XII of the periodic table of elements. In some embodiments, such salts are prepared using sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly preferred salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases with which salts can be obtained include, for example, primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

Pharmaceutically acceptable salts of this invention can be synthesized from basic or acidic fragments by conventional chemical methods. Usually, such salts can be obtained by reacting the free acid forms of the specified compounds with a stoichiometric amount of the corresponding bases (such as hydroxides, carbonates, bicarbonates, or the like of Ma, Ca, Mo, or K), or by reacting the free base forms of the specified compounds with stoichiometric amount of the corresponding acid. Such reactions are usually carried out in water, or in an organic solvent, or in a mixture of both. Of course, the use of non-aqueous media such as ether, 60 ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred if possible. Lists of additional suitable salts can be found, for example, in Ketipd(opie Rpappaseshis! Zsiepse5), 201p ey.,

Musk Rybiizpipd Sotrapu, Eazyup, Ra., (1985); and in "Naparook oi Riapgtaseshiisai! Zak: Rhorektiev, zeiIesip, apa Ove" Bu ani apa Meptshii (UMieu-msy, Ueippeit, Septapu, 2002).

When a basic group and an acidic group are both present in the same molecule, the compounds of this invention can also form internal salts, for example, zwitterionic molecules.

Any formulas presented in the description also represent unlabeled forms, as well as isotopically labeled forms of the compounds in question. Isotopically labeled compounds have the structures depicted by the formulas presented, except that one or more of the atoms is replaced by an atom of the chosen atomic weight or mass number. Examples of isotopes that may be included in the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H, ЗН, "С, 7190, 140, 195M, 8, zr, z2p, 355 , 360, 125I, respectively. The present invention includes various isotope-labeled compounds as defined in the description, for example, those with radioactive isotopes such as H and "C, or those with non-radioactive isotopes such as 2H and " 30. Such isotope-labeled compounds can be used in studies of metabolism (with "C"), in studies of reaction kinetics (for example, with "H or ZH), in methods of detection or obtaining images, such as positron emission tomography (PET) or single-flow emission computed tomography (CT), including analyzes of the distribution of drugs or substrates in tissues, or during radioactive treatment of patients. In particular, "E" or compounds labeled "E" may be particularly useful for PET or

GROWTH of research. Isotopically labeled compounds of formula (I) may generally be prepared by conventional methods well known to those skilled in the art, or by methods analogous to those disclosed in the attached Examples and Preparation sections, using appropriate isotopically labeled reagents instead of the unlabeled reagents previously used.

In addition, substitution with heavier isotopes, especially deuterium (i.e., "H or 0), may provide some therapeutic advantages due to higher metabolic stability, such as increased half-life, or reduced doses, or improved therapeutic index. It should be understood that deuterium in this context is considered as a substitute for the compound of formula (I). The concentrations of such heavy isotopes, especially deuterium, can be

To be determined by the coefficient of isotopic enrichment. The term "isotopic enrichment factor" as used herein means the ratio between the concentration of an isotope and the natural concentration of said isotope. When a substituent in a compound of the present invention is specified as deuterium, such compound has an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5 95 deuterium incorporation into each specified deuterium atom), at least 4000 (60 96 deuterium incorporation), at least 4500 (67 .5 95 deuterium inclusion), at least 5000 (75 95 deuterium inclusion), at least 5500 (82.5 Fo deuterium inclusion), at least 6000 (90 95 deuterium inclusion), at least 6333.3 (95 Fo deuterium inclusion), at least 6466, 7 (97 96 deuterium inclusion), at least 6600 (99 96 deuterium inclusion), or at least 6633.3 (99.5 95 deuterium inclusion).

Pharmaceutically acceptable solvates in accordance with 3 of the present invention include those in which the solvent of crystallization can be isotopically substituted, for example, O2O, dv-acetone, dv-

DMSO.

Compounds of this invention, which contain groups capable of acting as donors and/or acceptors for hydrogen bonds, can form co-crystals with suitable co-crystal formers. Such co-crystals can be obtained from compounds of formula (I) by known methods of co-crystal formation. Such methods include grinding, heating, co-sublimation, co-melting or contacting in solution a compound of the formula | with a co-crystal former under conditions of crystallization and separation of co-crystals formed in this way. Suitable co-crystal formers include those disclosed in

MO 2004/078163. Therefore, in this invention, in addition, co-crystals including compounds of formula (1) are proposed.

The present invention also provides prodrugs of the compounds of the present invention, which are instantly converted into the compounds of the present invention. A prodrug is an active or inactive compound that is chemically modified as a result of a physiological action, such as hydrolysis, metabolism, etc., of a compound of the present invention after administration of the prodrug to a subject. The suitability and methods involved in the creation and use of prodrugs are well known to those skilled in the art. See Te Rgasiise oi Meadisipa! Spetivigu, SI. 31-32 (Ea.

Mep, Asadetis Rgez5, Zap Oyedo, Saiii., 2001).

In addition, the compounds of this invention, including their salts, can also be obtained in the form of their hydrates, or with the inclusion of other solvents used for their crystallization. The compounds of this invention can naturally or by synthesis form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention includes both solvates and unsolvated forms. The term "solvate" refers to molecular complexes of the compounds of this invention (including their pharmaceutically acceptable salts) with one or more of the solvent molecules. Such solvent molecules are commonly used in the field of pharmaceuticals, which are known to be harmless to the recipient, for example, water, ethanol, etc.

The term "hydrate" refers to complexes in which the solvent molecules are water. The compounds of this invention, including salts, hydrates and solvates thereof, may naturally or by design form polymorphs.

Preferred substituents, preferred ranges of numerical values, or preferred range of radicals present in the compounds of formula I and corresponding intermediate compounds are defined below. The definitions of substituents are applicable to the final products as well as to the corresponding intermediates. The definitions of substituents can be combined if desired, for example with preferred substituents A and especially preferred substituents Ki.

In one embodiment, the present invention provides a compound of formula I, where EC: represents

C:-alkyl, C3-'ecycloalkyl, C3-ecycloalkyl-C:-halkyl.

In one embodiment, the present invention provides a compound of formula I, where EC: represents

C3-alkyl or C3-cycloalkyl.

In one embodiment, the present invention provides a compound of formula I, where EC: is isopropyl, cyclopropyl, cyclobutyl or cyclopentyl.

In one embodiment, the present invention provides a compound of formula I, where B is isopropyl. In one embodiment, the present invention provides a compound of formula I, where K: is cyclobutyl.

In one variant, the present invention provides a compound of formula I, where t is 1.

In one variant, the present invention provides a compound of formula I, where t is 2.

In one embodiment, the present invention provides a compound of formula III, where n is 0, 1 or 2, and where each E2 is independently halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyl

Zo group, C1-halogenalkoxy group or C3-acycloalkyl; or two Co near the same carbon atom together with the indicated carbon atom form C3.acycloalkyl.

In one variant, the present invention provides a compound of formula I, where n represents 0.

In one embodiment, the present invention provides a compound of formula I, where X: represents oxygen. In one embodiment, the present invention provides a compound of formula I, where Xy represents -M(Va)-, and Ka represents hydrogen, C1-alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C6-alkyl.

In one variant, the present invention proposes a compound of formula I, where X: represents -

M(Ba4)-, and Ka is hydrogen.

In one embodiment, the present invention provides a compound of formula II, where p is 1 and d is 1.

In one variant, the present invention provides a compound of formula I, where p is 0 and d is 1.

In one embodiment, the present invention provides a compound of formula II, where p is 0 and d is 0.

In one embodiment, the present invention provides a compound of the formula Y, where r is 0, 1 or 2, and where each Ez independently represents halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyl, C1-4haloalkyl, or C3.acycloalkyl; or two Kz near the same carbon atom form together with the specified carbon atom C3.acycloalkyl.

In one embodiment, the present invention provides a compound of formula I, where r is 0.

In one embodiment, the present invention provides a compound of formula I, where A is

JSC

Sq

AND

Shk

Sam (AT); where the bond marked with an asterisk is attached to the nitrogen atom.

In one embodiment, the present invention provides a compound of formula I, where A is

A1; B5 is hydrogen, C:-alkyl, C1-haloalkyl or C3-cycloalkyl; 5 is 0, 1 or 2; and each R is independently halogen, C 3 -alkyl, C 1 -haloalkyl, C 1 -alkoxy, C 1 -haloalkyl, or C 3 -acycloalkyl.

In one embodiment, the present invention provides a compound of formula I, where A is

A1, H5 is hydrogen or methyl, and 5 is 0.

In one embodiment, the present invention provides a compound of formula I, where A is

Ag her av ay ex 7 (A2); where the bond marked with an asterisk is attached to a nitrogen atom; and 5 represents 0, 1, or 2.

In one embodiment, the present invention provides a compound of formula I, where A is

Ag;

Vo represents hydrogen, C-alkyl, C:-haloalkyl or C3-acycloalkyl; 5 represents 0, 1 or 2; and each R is independently halogen, C 3 -alkyl, C 1 -haloalkyl, C 1 -alkoxy, C 1 -haloalkyl, or C 3 -acycloalkyl.

In one embodiment, the present invention provides a compound of formula I, where A is

Ah,

B5 is hydrogen or methyl, and 5 is 0.

In one embodiment, the present invention provides a compound of formula I, where A is

AZ no

And so on

Se same (AZ); where the bond marked with an asterisk is attached to the nitrogen atom.

In one embodiment, the present invention provides a compound of formula I, where A is

AZ;

Vo represents hydrogen, C-alkyl, C:-haloalkyl or C3-acycloalkyl; 5 represents 0, 1 or 2; and each K is independently a halogen, C1-alkyl, C1-haloalkyl, C1-6 alkoxy group, C1-haloalkyloxy group, or C3-acycloalkyl.

In one embodiment, the present invention provides a compound of formula I, where A is

AZ, H5 is hydrogen or methyl, and 5 is 0.

In one embodiment, the present invention provides a compound of formula I, where A is

AD ate ka

J Czech x (A4); where the bond marked with an asterisk is attached to a nitrogen atom; and 5 represents 0, 1, or 2.

In one embodiment, the present invention provides a compound of formula I, where A is

Hell;

Vo represents hydrogen, C-alkyl, C:-haloalkyl or C3-acycloalkyl; 5 represents 0, 1 or 2; and each C is independently halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy group, C 1-3 haloalkyloxy group, or C 3-acycloalkyl.

In one embodiment, the present invention provides a compound of formula I, where A is

A4, N is hydrogen or methyl, and 5 is 0.

In one variant, the present invention provides a compound of formula I, where EC: represents isopropyl or cyclobutyl; t is 1; n represents 0, 1 or 2; each Co independently

B is a halogen, C3-alkyl, C:-haloalkyl, C:-4-alkoxy group, C:1-haloalkoxy group or

C3.acycloalkyl; or two KE" near the same carbon atom together with the indicated carbon atom form C3-cycloalkyl;

Chi is oxygen; p represents 1, and d represents 1; 10 g is 0, 1 or 2; where each Kz independently represents a halogen, C1-4alkyl, C1-haloalkyl, C1-4-alkoxy group,

C: .«halogenoxy group or C3.«-cycloalkyl; or two Kz near one and the same carbon atom form C3-cycloalkyl together with the indicated carbon atom; And choose from AZ and A4

IN

M o t ka o sia (Kv)v | about the same (Ko)e 15 (AB); Xia (A4); where the bond marked with an asterisk is attached to a nitrogen atom;

B5 is hydrogen or methyl; is 0, 1 or 2; and each K is independently halogen, C3-alkyl, C1-haloalkyl, C1-alkoxy group, C1-halohaloalkyl or C3-acycloalkyl;

In one embodiment, the present invention provides a compound of formula I, where

B: is isopropyl or cyclobutyl; t represents 1, and n represents 0;

Chi is oxygen; p represents 1, and d represents 1; r is 0; and A are chosen from AZ and A4

V and c) and kar o

Р(Вех и кд ж Ж (Ко) (АВ); Сх (А4); where the bond marked with an asterisk is attached to a nitrogen atom; and K5 is hydrogen or methyl; and 5 is 0.

In one embodiment, the present invention provides a compound of formula I, where EC: represents

C:-alkyl or C3-ecycloalkyl; t represents 1 and n represents 0;

Chi is oxygen; p represents 1, and d represents 1; r is 0; and

A represents itself

kk'

M yuyu k Kk

M and Veh where the bond marked with an asterisk is attached to the nitrogen atom;

Xg is nitrogen or carbon;

B5 is hydrogen or C-alkyl; and 5 represents 0.

In one embodiment, the present invention provides a compound of formula I, where EC: represents

C:-alkyl or C3-ecycloalkyl; t represents 1, and n represents 0;

Chi is oxygen; p represents 1, and d represents 1; r is 0; and

And they choose from AZ and A4 and not her 0 o age b

Same Same (Kv)" (AB); (A4); where the bond marked with an asterisk is attached to a nitrogen atom;

B5 is hydrogen or C-alkyl; and 5 represents 0.

In one embodiment, the present invention provides a compound of formula I, where

B: is isopropyl, cyclopropyl or cyclobutyl; t represents 1, and n represents 0;

Chi is oxygen; p represents 1, and d represents 1; r is 0; and

A represents itself

KE and no 7 Kk da veu where the bond marked with an asterisk is attached to the nitrogen atom;

Xg is nitrogen or carbon;

B5 is hydrogen, methyl or ethyl; and 5 represents 0.

In one embodiment, the present invention provides a compound of formula I, where

B: is isopropyl, cyclopropyl or cyclobutyl; t represents 1, and n represents 0;

Chi is oxygen; p represents 1, and d represents 1; r is 0; and A are chosen from AZ and A4

Kk; and

M. o (ved b (AZ); same (A4); where the bond marked with an asterisk is attached to the nitrogen atom;

B5 is hydrogen, methyl or ethyl; and 5 represents 0.

In the best variants, the present invention relates to one or more of the compounds of formula I, listed below in the examples section, or to their salts.

In addition, examples of suitable compounds of this invention are compounds selected from the following group P.

Group P: suitable compounds of this invention: 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate; 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-isopropyl-piperazine-1-carboxylate; 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate; 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclopropylpiperazine-1-carboxylate;

1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutyl-piperazine-1-carboxylate; 1-(1-ethyl-6-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl 4-isopropylpiperazine-1-carboxylate; 1-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate; 1-(2-oxo-1 2-dihydropyridin-4-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate; 1-(2-oxo-1 2-dihydropyridin-4-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate; or 1-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate; or salts of these compounds.

In the next aspect, the present invention proposes a method of obtaining compounds of the formula

I-1. Compounds of formula 1-1 can be prepared in the following manner as disclosed in Scheme 1:

Scheme 1: (owners (Bug and MN (Vu)g

And what about Ya7A

Yes; H

KV; what did you drink

A 1 ia:

Compounds of formula 1-1, in which A, Ki, He", Nz, t, p, p, d and g take the values indicated for formula I, can be obtained by carrying out the interaction of compounds of formula 1I-1, in which A, Kz, p, 4, and d take those specified for the formula | value, and Ka represents a leaving group, for example, halogen, such as chlorine, or 4-nitrophenyloxy (preferably, if Ka is 4-nitrophenyloxy), with a compound of formula I, in which Ki, H2, m and n are taken as indicated for formulas | value, in the presence of a suitable base, for example, diisopropylethylamine, In the presence of a suitable solvent, for example, pyridine.

In the next aspect, the present invention also proposes a method of obtaining compounds of formula 1-2. Compounds of formula 1-2 can be prepared according to the following method, as disclosed in Scheme 2:

Scheme 2: (b

As (yam da A V o shcha o rah (vip tsa in tr

N.M. r. n i r zt 2 2

Compounds of formula 1-2, in which A, Ki, He", Nz, t, n, p, d and g take the values specified for formula I, can be obtained by carrying out the interaction of compounds of formula 1I-2, in which A, Kz, p, 4 and d take those specified for formula I! value, with the compound of the formula IP, in which Ki, B, t and n

Zo accept those specified for formula I! value, in the presence of carbonyldiimidazole, a suitable base, for example, diisopropylethylamine, and a suitable solvent, for example, dimethylformamide.

In addition, compounds of formula I or their precursors can be obtained from compounds of formulas 1-1 or I1-2, obtained in accordance with schemes 1 or 2, or their precursors (for example, compounds of formulas

I-1, 1-2 and/or II), by reduction, oxidation and/or other methods of functionalization of the obtained compounds and/or by removal of optionally present protective groups, and isolation of compounds of formula I thus obtained.

Compounds of formula I can also be obtained by conventional methods, for example, those disclosed in the examples section, and these methods, in addition, represent aspects of the present invention.

The present invention also implies that compounds of formula (I) can be obtained as a result of direct biotransformations from prodrugs.

These reactions can be carried out by conventional methods, for example, as disclosed in the examples section.

Treatment of reaction mixtures and purification of compounds thus obtained can be carried out in accordance with known methods.

Addition salts of acids can be obtained from free bases by known methods, and vice versa.

The starting materials, for example, compounds of formulas 1I-1, 1I-2 and II, may be known, or they may be obtained by conventional methods starting from known compounds, for example, as disclosed in the examples section.

In the next aspect, this invention also proposes a method of obtaining compounds of formula 1I-14. Compounds of formula 1I-1 can be obtained in accordance with the following method, as disclosed in Scheme 3:

Scheme 3: (k,)g (B3zh k.shCHOV, (kg (pa mn A im z d fo AVu nn (tk tn spa no r Stage 3.1 Stage 3.2 X

BUT gy Kk: o r

Uk a

M

Stage 3.1: Compounds of the formulas U-1, in which A, Kz, p, 4, and g take the values specified for the formula, can be obtained by reacting compounds of the formula MII-1, in which Kz, p, 4, and g take the values specified for the formula And values, with compounds of the formula MI, in which A takes the previously indicated for the formula | value, and K is halogen, for example chlorine, in the presence of a suitable base, for example diisopropylethylamine, and optionally in the presence of a suitable solvent.

Stage 3.2: Compounds of formula 1I-1, in which А, Ки, ВН», Вз, т, п, р, д and г take the values specified for formula I, can be obtained by reacting compounds У-1 with compounds of the formula

IMs in which Ks is halogen, for example chlorine, and Ka is a leaving group, for example halogen or 4-nitrophenyloxy (preferably Ka is 4-nitrophenyloxy), in the presence of a suitable base, for example isopropylethylamine, and in the presence of a suitable solvent , for example, pyridine.

In the next aspect, the present invention also proposes new compounds of the formula 1I-1 (Ks

AND

Khy o R (P-7); or their salts; in which p, ad, r, Ez and A take the values specified for formula I; Ka represents a leaving group, for example, a halogen such as chlorine, or a group selected from o; 7

In , /. ; As

Di ts ay M-eo M « 0 is - Mashi o and where the bond marked with an asterisk is attached to the carbonyl group; where K is a hydrogen or nitro group; mostly Ka is a 4-nitrophenyloxy group.

In one variant of the following aspect, the present invention proposes a compound of formula 1I-1, where p is 1, and d is 1; p represents 0, and d represents 1; or p represents 0, and d represents 0; r is 0, 1 or 2, and where each B2 is independently halogen, C1-4alkyl, C1-4haloalkyl, C1-4haloalkyl, C1-4haloalkyl or C3-4cycloalkyl, or two E2 near of the same carbon atom form together with the specified carbon atom C3.cycloalkyl; and

A is A4 or AB.

In one variant of the following aspect, the present invention proposes a compound of formula 1I-1, where K: represents isopropyl; t is 1; Chi is oxygen; p represents 1, and d represents 1; n represents 0; p represents 1, and d represents 1; A is A4 or Ab5; and 5 is hydrogen or methyl.

In one variant of the following aspect, the present invention proposes a compound of formula 1I-1, where K: represents cyclobutyl; t is 1; Chi is oxygen; p represents 1, and d represents 1; n represents 0; p represents 1, and d represents 1; A is A4 or Ab5; and 5 is hydrogen or methyl.

In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier. Said pharmaceutical compositions can be designed for a specific route of administration such as oral administration, parenteral administration and rectal administration, etc. In addition, the pharmaceutical compositions of this invention can be prepared in solid form, including capsules, tablets, pills, granules, powder or suppositories, or in liquid form, including solutions, suspensions or emulsions. Such pharmaceutical compositions may be subjected to conventional pharmaceutical operations, such as sterilization, and/or they may contain conventional inert diluents, lubricating agents or buffering agents, as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc. d.

Of course, pharmaceutical compositions are tablets and gelatin capsules that include the active ingredient together with a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;

C) lubricating agents, for example, silicon dioxide, talc, stearic acid, their magnesium or calcium salts, and/or polyethylene glycols; for tablets also c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone; and if desired a) leavening agents, for example, starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, dyes, fragrances and sweeteners.

The tablets may be coated with either a film or an enteric coating by methods known to those skilled in the art.

Suitable compositions for oral administration include an effective amount of a compound of this invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral administration are prepared by any of the methods well known to those skilled in the art of pharmaceutical formulation, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives to obtain pharmaceutical elegant and pleasant-tasting preparations. Tablets contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; grinding agents and leavening agents such as corn starch or alginic acid; binding agents, for example, starch, gelatin or acacia resin; and lubricating agents such as magnesium stearate, stearic acid or talc. Such tablets may be uncoated or coated in a manner known to those skilled in the art to delay disintegration and absorption in the gastrointestinal tract and thereby provide a delayed action over a longer period of time. For example, retarding materials such as glycerol monostearate or glycerol distearate can be used. Pharmaceutical compositions for oral administration may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oily medium such as peanut oil, liquid paraffin or olive oil.

Some compositions for injections are aqueous isotonic solutions or suspensions, and suppositories, which are preferably obtained from fatty emulsions or suspensions. Said compositions can be sterilized and/or they can contain adjuvants such as preservatives, stabilizing, wetting or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.

Said compositions are prepared using conventional methods of mixing, granulation, coating, respectively, and they contain about 0.1-75 95, or contain about 1-50 95, of the active ingredient.

Suitable compositions for transdermal use include an effective amount of a compound of this invention with a carrier. Carriers include absorbable pharmacologically acceptable solvents that promote penetration through the host's skin. For example, transdermal devices may be in the form of bandages that include a support member, a reservoir containing said compound, optionally with a carrier, optionally a rate-controlling barrier to deliver the compound through the skin of the host at a controlled and predetermined rate over an extended period of time. a period of time, and means for fixing the equipment on the skin.

Suitable compositions for external use, e.g. for skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or spray compositions, e.g. for delivery via aerosols or the like. Such external delivery systems are particularly suitable for application to the skin, e.g. for the treatment of skin cancer, e.g. for prophylactic use in sunscreens, lotions, sprays, etc.

They are also particularly suitable for use in topical formulations, including cosmetics, well known to those skilled in the art. Such agents may contain solubilizers, stabilizers, tonicity agents, buffers, and preservatives.

As used herein, the term external administration may also refer to inhalation or intranasal administration. Drugs are usually supplied in the form of dry powder (either separately or in the form of a mixture, for example a dry mixture with lactose, or in the form of mixed particles, for example with phospholipids) from dry powder inhalers or in the form of aerosol sprays coming from pressurized containers, pumps, spray, atomizer or nebulizer, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceutical compositions and dosage forms containing the compounds of the present invention as active ingredients because water can facilitate the decomposition of some compounds.

Anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low moisture ingredients under low moisture or low humidity conditions. Anhydrous pharmaceutical compositions can be prepared and stored in such a way that their anhydrous nature is preserved. Accordingly, anhydrous compositions are preferably packaged using materials known to protect against contact with water, and are usually included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foil, plastics, unit dose containers (eg, ampoules), blister packs, and tape packaging.

The present invention further provides pharmaceutical compositions and dosage forms that include one or more agents that reduce the rate at which a compound of the present invention degrades as an active ingredient. Such agents, referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, and the like.

As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (eg, antibacterial agents, antifungal agents), isotonic agents, absorption retarding agents agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrating agents, lubricating agents, sweetening agents, flavoring agents, coloring agents, such similar materials and combinations thereof as are known to those skilled in the art (see, for example, Keptipdiopye Rpagtaseshisa!5siepse5, 181p

Ed. Mask Riipiitbud Sotrapu, 1990, 1289-1329). Except where any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is unacceptable.

Compounds of the formula 1/ or their pharmaceutically acceptable salts exhibit valuable pharmacological properties and can therefore be used as medicinal products.

In addition, the compounds of formula I may be useful for the study of NH receptors, for example, as tool compounds.

In particular, the compounds of formula I have an antagonistic effect on human NH receptors.

As used herein, the term "NO receptor antagonist" includes inverse NO receptor antagonists and neutral NO receptor agonists.

Antagonistic activity at NZ receptors can be determined by immunoassay, for example, at recombinant human NZ receptors, using various procedures, such as, for example, measuring inhibition of an agonist-induced increase in intracellular

CAMP concentration, for example, as disclosed in the description.

Therefore, the compounds of this invention may be useful for the prevention, treatment or retardation of the development of disorders mediated by NZ receptors. Disturbances mediated by NZ receptors can be such as, for example, i) sleep disturbances and wakefulness with excessive daytime sleepiness; such as narcolepsy, for example, narcolepsy with or without catalepsy; secondary narcoleptic syndromes; sleep apnea of central origin; or obstructive sleep apnea syndrome; ii) disorders or conditions associated with increasing obesity or hypersomnolence; such as obesity associated with autoimmune diseases such as multiple sclerosis or rheumatoid arthritis; obesity associated with neurodegenerative disorders, for example, such as Parkinson's disease, polysystemic atrophy, Shea-Drager syndrome or progressive supranuclear palsy syndrome; obesity associated with other medical conditions or their treatment, such as depression, emotional burnout, or adjustment disorders; stress-related disorders with accompanying obesity, such as acute stress disorders or post-traumatic stress disorders; cancer-related obesity; chemotherapy-related obesity; obesity associated with shift work; with the change of time zones; chronic obesity syndrome; fibromyalgia; post-infection obesity; postoperative obesity or dizziness; ii) disorders or conditions with disorders of consciousness; such as Alzheimer's disease; moderate cognitive impairment; dementia with Lewy bodies; vascular dementia; Huntington's disease; disease

Wilson; frontotemporal dementia; other forms of organic dementia or organic cognitive

From violation; multiple sclerosis; schizophrenia; schizoaffective disorders; bipolar affective disorder; to them) violations related to substance abuse or addiction; such as dependence on alcohol, cocaine, opioids, cannabinoids, nicotine or other substances of abuse or potential dependence; m) intangible states of abuse; such as pathological gambling addiction; mi) disorders associated with dysfunctional eating disorders and/or metabolic syndrome; such as weight gain associated with antipsychotic medications; Prader-Willi syndrome (Rgadeg-Umiii-Zpagote); Moon-Bardet-Biddle syndrome (Moop-

Vahayei-Vivdi Zupagote); adiposity; atypical depression; neurogenic bulimia; or compulsive overeating; mii) disorders with increased anxiety; such as general anxiety; social anxiety; or panic anxiety; mii) other neuropsychiatric or neuropathological disorders; such as Tourette syndrome; primary tic; secondary tic; attention deficit hyperactivity disorder; obsessive-compulsive disorders; headache, such as episodic migraine, chronic migraine, cluster headache, or tension headache; acute disorders associated with the loss of neurons, for example, a stroke; repeated sleep disturbance; restless legs syndrome; or epilepsy; i) other medical conditions or disorders; such as attention disorders; vertigo; Meniere's disease; scabies; itching; pain during inflammation; neuropathic pain; diabetes; cancer; atherosclerosis; allergies; or allergic rhinitis. Of particular importance is the treatment of narcolepsy; obesity associated with multiple sclerosis; fatigue associated with the disease

Parkinson's; cognitive impairment associated with schizophrenia; cognitive impairment associated with Alzheimer's disease; moderate cognitive impairment; Tourette syndrome; or attention deficit hyperactivity disorder.

For the indications (conditions and disorders) described above, appropriate doses may vary depending on, for example, the compound used, the host, the route of administration, and the nature and severity of the condition to be treated. However, generally satisfactory results in animals are achieved at daily doses of from about 0.001 to about 500 mg/kg body weight, preferably from about 0.1 to about 10 mg/kg body weight, for example 1 mg/kg for large animals, e.g. ,

humans, the indicated daily dose is in the range of from about 0.1 to about 1000 mg, preferably from about 0.1 to about 400 mg, most preferably from about 0.1 to about 100 mg of a compound of the present invention administered routinely, e.g. in separate doses up to four times a day.

For use in accordance with the present invention, a compound of the present invention can be administered as a single active agent or in combination with other active agents, by any conventional route, for example orally, for example in the form of tablets or capsules, or parenterally, for example in the form of solutions for injections or suspensions. A combination that includes a compound of this invention and one or more of other therapeutically active agents is referred to as a "combination of this invention."

In the case of narcolepsy, the compound of this invention can be combined with at least one active agent selected from the group consisting of a norepinephrine-dopamine reuptake inhibitor, such as modafinil or armodafinil; a tri- or tetracyclic antidepressant such as clomipramine; a serotonin-norepinephrine reuptake inhibitor such as venlafaxine or duloxetine; a selective serotonin reuptake inhibitor such as paroxetine; a norepinephrine reuptake inhibitor such as reboxetine or atomoxetine; an MAO-B inhibitor such as selegiline; gamma-hydroxy-butyrate; and a psychostimulant such as methylphenidate.

These combinations of the present invention can be used to treat narcolepsy.

In the case of fatigue associated with multiple sclerosis, the compounds of this invention can be combined with at least one active agent selected from the group consisting of a sphingosine-1-phosphate analog, such as fingolimod; and another immunosuppressive agent such as prednisone or methotrexate.

In the case of fatigue associated with Parkinson's disease, a compound of the present invention can be combined with at least one active agent selected from the group consisting of I-Ror

Co) with or without a decarboxylase inhibitor, such as benserazide or carbidopa, and/or with or without a catechol-O-methyltransferase inhibitor, such as entacapone or tolcapone; a dopamine receptor agonist such as ropinirole or pergolide; and an MAO-B inhibitor such as selegiline.

In the case of cognitive impairment associated with schizophrenia, the compound of this invention can be combined with at least one antipsychotic agent, such as haloperidol, olanzapine; risperidone; quetiapine; amisulpiride; or aripyrazole.

In the case of cognitive impairment associated with Alzheimer's disease, the compound of this invention can be combined with at least one active agent selected from the group consisting of cholinergic agents, such as an acetylcholinesterase inhibitor, for example, donepezil, rivastigmine or galantamine; and antiglutamatergic agents such as memantine, selfotel, or midafotel.

In the case of cognitive impairment associated with Alzheimer's disease, a compound of the present invention can be combined with at least one active agent selected from the group consisting of a cholinergic agent such as an acetylcholinesterase inhibitor, e.g., an acetylcholinesterase inhibitor, e.g., donpersil, rivastigmine or galantamine; and an antiglutamate agent such as memantine.

In the case of Tourette's syndrome, the compound of this invention can be combined with at least one active agent selected from the group consisting of an alpha-receptor agonist, such as clonidine; an antipsychotic agent such as fluphenazine, haloperidol, pimozide, aripyrazole, or risperidone; and a dopamine-depleting agent such as tetrabenazine.

In the case of attention deficit hyperactivity disorder, the compound of the present invention can be combined with at least one active agent selected from the group consisting of a norepinephrine-dopamine reuptake inhibitor, such as modafinil or armodafinil; a tri- or tetracyclic antidepressant such as clomipramine; because of a psychostimulant such as methylphenidate;

a norepinephrine-serotonin reuptake inhibitor such as venlafaxine or duloxetine; a selective serotonin reuptake inhibitor such as paroxetine; and a norepinephrine reuptake inhibitor such as reboxetine or tomoxetine.

The compounds of the present invention may be useful in the prevention of the conditions and disorders mentioned above.

The compounds of the present invention may be useful in the treatment of the conditions and disorders mentioned above.

The compounds of the present invention may be useful in delaying the development of the above-mentioned conditions and disorders.

The effectiveness of the compounds of this invention in the treatment of the disorders mentioned above can be confirmed in various standard tests, including those listed below:

The activity of the compounds of this invention can be assessed by measuring effects on brain histamine release (quantifying the histamine metabolite tele-methylhistamine) and/or testing effects on wakefulness in rats with EEO electrodes.

The compounds of this invention may be particularly useful in the treatment of indications selected from: narcolepsy; fatigue associated with multiple sclerosis; fatigue associated with Parkinson's disease; cognitive impairment associated with schizophrenia; cognitive impairment associated with Alzheimer's disease; moderate cognitive impairment; Tourette syndrome; and attention deficit hyperactivity disorder; and especially narcolepsy.

Thus, in addition to the specified variants, the present invention proposes the use of the compound of formula (I) or its pharmaceutically acceptable salt as a medicinal product.

Thus, in addition to the specified options, this invention proposes the use of the compound of formula (I) or its pharmaceutically acceptable salt in therapy.

In another embodiment, the therapy is selected from diseases that can be alleviated by inhibiting the action of NZ receptors. In another variant, the disease is selected from the list mentioned above, for example, selected from narcolepsy; fatigue associated with multiple sclerosis; fatigue associated with Parkinson's disease; impairment of cognitive functions associated with

With schizophrenia; cognitive impairment associated with Alzheimer's disease; moderate cognitive impairment; Tourette syndrome; and attention deficit hyperactivity disorder; and especially narcolepsy.

In another variant, the present invention provides a method of treating a disease that is alleviated by inhibiting NZ receptors, which includes the administration of a therapeutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another variant, the disease is selected from the list mentioned above, for example, selected from narcolepsy; fatigue associated with multiple sclerosis; fatigue associated with Parkinson's disease; cognitive impairment associated with schizophrenia; cognitive impairment associated with Alzheimer's disease; moderate cognitive impairment; Tourette syndrome; and attention deficit hyperactivity disorder; and especially narcolepsy.

The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that causes a biological or medical response in a subject, such as reducing or inhibiting the activity of an enzyme or protein, or alleviating symptoms, ameliorating conditions, slowing or delaying the progression of a disease, or disease prevention, etc. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective in (1) at least partially attenuating, inhibiting, preventing, and/or ameliorating a condition or disorder or a disease (i) mediated by NZ receptors, or (i) associated with the activity of NZ receptors, or (ii) characterized by abnormal activity of NZ receptors; or (2) reducing or inhibiting the activity of NZ receptors; or (3) reducing or inhibiting the expression of NH receptors.

In another non-limiting variant, the term "therapeutically effective amount" refers to such an amount of a compound of this invention, which, when introduced into a cell, or tissue, or non-cellular biological material, or environment, is effective in at least partially reducing or inhibiting the activity of NH receptors; or at least a partial reduction or inhibition of the expression of NH receptors.

As used herein, the term "subject" refers to animals. Preferably, if the animal is a mammal. The term subject also refers, for example, to primates

(eg humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In the preferred version, the subject is a person.

As used herein, the term "inhibition" or "inhibiting" refers to the reduction or suppression of a particular condition, symptom or disorder, or disease, or to a significant reduction in the baseline activity of a biological activity or process.

As used herein, the term "treating" or "treating" any disease or disorder refers in one embodiment to ameliorating the disorder or disease (ie, slowing or stopping or reducing the progression of the disease, or at least one of its clinical symptoms). In another embodiment, "treatment" or "treatment" refers to the alleviation and reduction of at least one physical parameter, including those that the patient may not experience. In yet another embodiment, the term "treatment" or "treatment" refers to modulating a disease or disorder either physically (e.g., by stabilizing a symptom imperceptible to the patient), physiologically (e.g., by stabilizing physical parameters), or both. In yet another embodiment, the term "treatment" or "treatment" refers to preventing or delaying the onset and development or progression of a disease or disorder.

The pharmaceutical compositions or combinations of the present invention may be in a unit dose of about 1-1000 mg of active ingredient(s) for subjects weighing about 50-70 kg, or about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients. Therapeutically effective doses of the compounds, pharmaceutical compositions, or combinations thereof depend on the type of subject, body weight, age, and individual condition of the disorder or disease to be treated or their severity. Physicians, clinicians, or veterinarians skilled in the art can readily determine the effective amount of each of the active ingredients needed to prevent, treat, or inhibit the development of a particular disorder or disease.

The properties of the above dosages can be demonstrated in ip miigo and ip mimo tests using primarily mammals, such as mice, rats, dogs, monkeys, or isolated organs, tissues, and preparations thereof. The compounds of this invention can be administered intravenously in the form of solutions, for example, preferably aqueous solutions, and intravenously or enterally or parenterally,

Preferably, intravenously, for example, in the form of a suspension or in an aqueous solution. The dose of ip migo can be between about 103 and 109 molar concentrations. A therapeutically effective amount of ip mimo can be, depending on the method of administration, between, for example, about 0.001-500 mg/kg, or between, for example, about 0.1-100 mg/kg.

The activity of the compound of the present invention can be evaluated by the methods disclosed in the description.

A compound of the present invention can be administered either simultaneously with or before or after at least one other therapeutic agent. The compound of this invention can be administered separately, by the same or different route of administration, or together in one pharmaceutical composition.

The following examples illustrate the present invention, but do not limit it.

Abbreviation:

VIMAR (-/-)-2,2'-bisidiphenylphosphino)-1,1-binaphthyl

Vos di(tert-butyl)carbonate

VTS triphosgene

OSM dichloromethane

PIREA M-ethyl-M-isopropylpropan-2-amine (diisopropylethylamine)

LOBSTER 4-dimethylaminepyridine

EA ethyl acetate h. hour(s)

NRGIS high performance liquid chromatography

LCMS liquid chromatography/mass spectroscopy

Meon methanol waves. minute(s)

NMR spectroscopy of nuclear magnetic resonance rger-NRI C preparative high-performance liquid chromatography

Rag(ava) with tris(dibenzylideneacetone)dipalladium(0)

The retention time is at room temperature

I1-ViOkK potassium tert-butanolate

TEA triethylamine or TEA trifluoroacetic acid

TNE tetrahydrofuran (THF)

LCMS conditions (95 - volume percent): Addiepi 1200 HPLC/system 6110 50; Mobile phase: A: water (10 mM MH.ANSO») B: acetonitrile; gradient: 595 V for 0.2 min., increase to 9595858 in 1.2 min.; 95,908 for 1.5 min., return to 5.95V in 0.01 min.; flow rate: 1.8 ml/min.; Column: KhVgidde C18, 4.6x50 mm, 3.5 μm; heater temperature: 5020.

NMR devices: Vgykeg AMAMSE PI (500 MHz), Vgykeg AMAMSE PI! (400 MHz)

Examples:

Example 1.1: 1-(6b-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl. 4-cyclobutyl-piperazine-1-carboxylate (Method A) o- t 1181 t Her (1197-95-31 / dk 2.0 m nHSEMeOH t

Vos-M MN ost bos change nm »

M-Shzhsh Mavn(ras)", and va

Sisnenoi, cl. and (143238-38-4) 10095

MO» yu-( in idu i sho sg o 0-5. IBzvalvy) 0-0 )chon (7693-46-1 ne-m PIREA, 13090 nm Rou, OSM, cl. po o - shi o languages nk- U -at

OKU se. uh uh she! TEA, OSM, cat. - a) tert-butyl 4-cyclobutylpiperazine-1-carboxylate fl:

Vos-M OM-0" she

To a solution of tert-butyl piperazine-1-carboxylate compound (37.2 g, 200 mmol) in NaCl (500 mL) was added cyclobutanone (21 g, 300 mmol) and Mavn(oOgds)"z (84.8 g, 400 mmol ). The reaction mixture was stirred at room temperature for 16 hours, quenched with a saturated aqueous solution of MagSbOz (500 ml) and extracted with USM (3x500 ml). The combined organic layers were washed with brine (50 mL), dried, filtered, and concentrated under reduced pressure to give the title compound, tert-butyl 4-cyclobutylpiperazine-1-carboxylate (48 g, 100 95) |LCMS: 1.67 min ., t/2 241.2 (MAN)UA. p) 1-cyclobutylpiperazine hydrochloride 2 on "I nm M-05"

To a mixture of tert-butyl 4-cyclobutylpiperazine-1-carboxylate (48 g, 200 mmol) in MeOnH (100 mL) was cautiously added 2.0N HCl in MeOnH (400 mL) at 02С. The mixture was stirred at room temperature for 5 hours, concentrated under reduced pressure, obtaining the target compound 1-cyclobutylpiperazine hydrochloride (35 g, 82 95) | LCMS: EC-0.94 min., pt/2 141.3 (MAN). c) 6-(4-hydroxypiperidin-1-yl)pyridazin-Z(2H)-one nMe-M

Piperidin-4-ol (2.4 g, 20 mmol) was added to a solution of b-chloropyridazine-Z(2H)-one (2.6 g, 20 mmol) in OIREA (30 ml), and the resulting mixture was stirred at 1202C for 8 hours . The reaction mixture was concentrated under reduced pressure, obtaining a crude product, which was further purified using chromatography on silica gel (ЮСМ/МеонН-20/1) to obtain the title compound (3.9 g, 100 95) as a yellow solid .

IRHMS: Ch-0.77 min., t/7 196.2 (MAN). a) 4-nitrophenyl 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-ylcarbonate in

NM. - MO"

SOSKAK about Fr

To a solution of 6-(4-hydroxypiperidin-1-yl)/pyridazin-Z(2H)-one (3.9 g, 20 mmol) in pyridine (10 mL) was added OIREA (3.87 g, 30.0 mmol) and 4-nitrophenyl chloroformate (6.03 g, 30 mmol), and the resulting mixture was stirred at 302C for 2 hours. The resulting mixture was concentrated under reduced pressure and the residue was purified using chromatography on silica gel (OSM to OSM/Meon:-20/1) to give the title compound (3.3 g, 46 9o) as a white solid.

IRKHMS: KCh-1.47 min., t/7 361.1 (MAN). f) 1-(6-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate by nn Um -5 according to Bl

TEA (616 mg, 6, 1 mmol) and 1-cyclobutylpiperazine (388 mg, 1.83 mmol). The resulting mixture is stirred at 302C for 2 hours before being concentrated to dryness. The title compound is obtained as a white solid after chromatography on silica gel (OSM/Meona:5Bol to 5/1) (410 mg, 93 vol). "IN NMR (400 MHz, SOSIv) b 11.20 (s, 1), 7.20 (d, 9-10 Hz, 1H), 6.87 (d, 9-10 Hz, 1H), 4.87 -4.92 (m, 1H), 3.45-3.50 (m, 6H), 3.16-3.23 (m, 2H), 2.68-2.76 (m, 1H), 2 .29 (lat. 4H), 1.72-2.07 (m, 10H); IRHMS: K-1.36 min., pt/: 362.3 (MN).

Example 1.2: 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl 4 isopropylpiperazine-1-carboxylate - d-yu, no-Mn-6 a Ca x o stv SNU, p53sOz 7 sovno PI "in don (gvvz-

M sn Im pIRAB, 12096 nan TIREA, VOM, WHO. si tv si vuh as 19085487) ih ch nok x Be n- - n-V m-n GU. Pii x S-a hi oyu doyu zn td, VsM o

Gee! 3

Zo a) b-chloro-2-methylpyridazin-Z(2H)-one p

Sho;

M

SI

To a solution of b-chloropyridazine-Z(2H)-one (780 mg, 6 mmol) in SNISM (40 ml) was added C520Oz (3.9 g, 12 mmol) and SnH2 (1 ml, 12 mmol) and the reaction mixture was stirred at 702С during the night. The solid part is removed by filtration, and the resulting filtrate is concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane/EA-3/1) to give the title compound as an orange oil (6.5 g, 75 95).

IRHMS: Ch-1.43 min., t/72 145.1 (MAN).

B) 6-(4-hydroxypiperidin-1-yl)-2-methylpyridazin-Z(2H)-one x -M

Piperidin-4-ol (0.84 g, 8.33 mmol) was added to a suspension of b-chloro-2-methylpyridazin-3(2H)-one (1 g, 6.94 mmol) in PIREA (20 mL), and the reaction mixture is stirred at 1202C overnight.

The resulting mixture is diluted with water (30 ml) and extracted with OSM (3x30 ml) to remove impurities. The aqueous phase was concentrated to dryness to give the title compound as a yellow solid (1.2 g, 83 95).

IRHMS: KCh-1.07 min., t/72 210.1 (MAN). c) 1-1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl 4-nitrophenyl carbonate

4-nitrophenyl chloroformate (2.11 g, 10 .5 mmol) and OIREA (1.81 g, 14 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with OCM (20 mL), washed with water (3x15 mL) and the organic layer was concentrated to give the title compound as a yellow solid (1.2 g, 46,965). |RHMS: K-1.54 min. t/2-:375.1 (MAN). a) 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-isopropyl-piperazine-1-carboxylate

Ha) i-6 mk Uk - podedany

To a solution of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl 4-nitrophenyl carbonate (1.2 g, 3.p2 mmol) in OSM (20 ml) is added 1-isopropylpiperazine (0.6 g, 4.8 mmol) and TEA (5 mL), and the reaction mixture was stirred at room temperature for

From the night The mixture is then washed with a saturated solution of MgSO3 (3x30 mL), dried and concentrated to give the crude product, which is purified using chromatography on silica gel (PE/EA-1/1) to give the title compound as a white solid (0 ,48 g, 41 9).

HN NMR (СосСИ», 400 MHz): b 7.13--7.10 (d, 9-10, 1Н), 6.86-6.84 (d, 9-10, 1Н), 4.92- -4.88 (m, 1H), 3.66 (s, ЗН), 3.51-3.46 (lat. 6H); 3.22--3.16 (m, 2H); 2.74-2.70 (m, 1H), 2.49 (width 4H), 1.99 (m, 2H), 1.75 (m, 2H), 1.04 (d, 6H); RHMS NKE-1.40 min., pt/: 364.2 (MAN).

Example 1.5: 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate, and Art. cyclobutyl-piperazine-1-carboxylate o

Zm-k I; i am

OIEA (105 mg, 0.81 mmol) and 1-cyclobutylpiperazine (56 mg, 0.40 mmol). The mixture is stirred at room temperature overnight before being diluted with 30 mL of water and extracted with OSM (3x25 mL). The combined organic phase is dried over anhydrous Mag250O54, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (Vioiade, reverse phase column C-18, MeOH/HgO-5 95-95 95, 0.5 956 MNAOH) to give 20 mg of the desired compound as a white solid.

GN NMR (SOSI", 400 MHz): b 7.12 (d, 9-10, 1H), 6.85 (d, 9-10, 1H), 4.94-4.88 (m, 1H), 3.67 (c, 10. ZN), 3.52-3.46 (m, 6H), 3.23-3.17 (m, 2H), 2.75-2.69 (m, 1H), 2.30 (width 4H), 2.08-1.97 (m, 4H), 1.93-1.686 (m, 2H), 1.82-1.68 (m, 4H); RHMS MEU1.44 min., t/2 376.3(MAN)Y.

Example 2: Synthesis of 1-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate (Method B)

NM in I meen ch: 7 - ? : 4318-42-7 --- from

Bob-m agho she zhk vek he I 2-71 Dos M-o -t-k, - sleep. VTS, LOBSTER, etc

G79099-07-3) at" TEA, OSM, cl. Mn ach sh writes: not V o sh- I Kh ih ha "IRA, OSM, ku. ol KI in Vvevzatya nnshka resi 10096 is shi TEA, 100s 7 dv, - o 1005 19: . dreams Kv

ZI. MAN, TE, kh nedo Yes, zo sa no I a) tert-butyl 4-hydroxypiperidine-1-carboxylate

Vos-kU-on

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (10 g, 50 mmol) in SNIZON (100 ml), Mavny (5.7 g, 150 mmol) was carefully added in portions, and the mixture was stirred at room temperature for 3 hours. The reaction is quenched by carefully pouring into a mixture of ice and water (100 mL) and the organic solvent is removed under reduced pressure. The aqueous phase is neutralized to rne-7, using other NSI, and extract OSM/Meon (5x60 ml, volume/06-10/1). The combined organic layers were washed with brine (30 mL), dried over anhydrous Ma250, filtered, and concentrated under reduced pressure to give the crude product (9.8 g, 97 95) as a white solid. |LCMS: EC-1.36 min., t/2 146.1 (M-Vy--NU. a) 1-"tert-butoxycarbonyl)piperidin-4-yl-isopropylpiperazine-1-carboxylate et

Ok about sl

OMAR (5.3 g, 43.8 mmol) and triphosgene (3.2 g, 10.95 mmol).

After stirring at room temperature for 2 hours, 1-isopropylpiperazine is added

Zo (3.3 g, 26 mmol) and the reaction mixture was stirred at room temperature for 5 hours.

The reaction is quenched with a saturated solution of MNACI (100 ml) and the mixture is extracted with OSM (3x100 ml).

The combined organic layers were washed successively with a saturated solution of MNACI (2 x 100 ml) and brine (50 ml), dried over anhydrous Mag5O»4, filtered and concentrated under reduced pressure, obtaining the title compound as a white solid (7, 7 g, 99 90). (LCMS: Ch-1.67 min., t/2 356.3 (MAAN)Y. p) piperidin-4-yl 4-isopropylpiperazine-1-carboxylate

M M about porridge

TEA (10 ml) was added to a solution of 1-(tert-butoxycarbonyl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate (7.7 g, 21.7 mmol) in OCM (30 ml) and the reaction mixture was stirred at room temperature. temperature for 5 hours. The solvent is removed under reduced pressure, and the residue is redissolved in OSM/MeoionH (100 ml, v/v - 10/1). Then Mag2CO3 powder is added and the mixture is stirred at room temperature for 2 hours. Excess MgCO3 is removed by filtration, and the filter cake is washed with SOCM (2 x 100 ml).

The combined filtrates were concentrated under reduced pressure to give the desired compound as a yellow oil (5.5 g, 100 95). |RHMS: KE-1.12 min., t/72 256.2 (MAN). c) 1-(2-oxo-1,2-dihydropyridin-4-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate

To a solution of 4-bromopyridin-2(1H)-one (173 mg, 1.0 mmol) in TEA (10 mL) was added piperidin-4-yl 4-isopropylpiperazine-1-carboxylate (255 mg, 1.0 mmol) and the resulting mixture is stirred at 1002C for 16 hours. After cooling to room temperature, the resulting mixture is concentrated in a vacuum. The residue is dissolved in OSM (50 ml) and the resulting mixture is washed with a saturated solution of Manso»z (2x30 ml). The organic layer was dried and concentrated to give the crude product (348 mg, 100 95), which was used directly in the next step without further purification.

IRHMS: KCh-1.27 min., t/7 349.2 (MAN). a) 1-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)piperidin-4-yl 4-isopropyl-piperazine-1-carboxylate

I) 3 - from m m- 900-

Man ( 60 95 in mineral oil) (200 mg, 5.0 mmol). After stirring at room temperature for 1 hour, CH2Cl (213 mg, 1.5 mmol) was added and the reaction mixture was stirred at room temperature

From within 5 hours. The reaction is quenched with water (30 ml), extracted with OSM (3x30 ml), dried and concentrated, obtaining a crude product, which is further purified using preparative

HPLC to give the title compound as a white solid (110 mg, 30 Vol).

HN NMR (500 MHz, SOSI»z) b 7.07 (d, 9U-8.0 Hz, 1H), 5.90 (dd, 9U-8.0, 2.5 Hz, 1H), 5, 77 (d, U-2.5

Hz, 1H), 4.89--4.94 (m, 1H), 3.47-3.52 (m, 6H), 3.44 (s, ЗН), 3.20-3.25 (m , 2H), 2.68--2.73 (m, 1H), 2.47 (width 4H), 1.92-1.98 (m, 2H), 1.69--1.76 (m , 2H), 1.04 (d, 9-6.5 Hz, 6H); RHMS: K-1.31 min., t/2 363.3 (M.N).

Example (3: 1-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-4-yl 4-isopropyl-piperazine-1-carboxylate (Method C) and what it

Really hu 0! i i tolhel, NVO Mav, raharan, VIMAR zavdya, I | VIK, tezuvya

Gzevv- povzeo) Microwaves. 120C, 30 min. 2095

СХ for ac; no"

Mo N» PIC M Her 1 " ot

MeOH, 10 min. ot rvoe Sm i t a) 2-(benzyloxy)-5-bromopyridine 4. xx

My

Hg

(Bromomethyl)benzene (1, 25 g, 7.36 mmol), and the reaction mixture was stirred at 1002 overnight. The reaction mixture is filtered through a thin layer of silica gel and washed with OCM. The resulting filtrate was concentrated to give the title compound as a light yellow oil (1.8 g, 95 Vol).

B) 1-(6-(benzyloxy)-pyridin-3-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate according to "M heavy

To a solution of 2-(benzyloxy)-5-bromopyridine (1.5 g, 5.mmol), piperidin-4-yl 4-isopropylpiperazine-1-carboxylate (2.15 g, 8.4 mmol) in toluene (30 ml) ) add Raz(ava)z (1.57 g, 2.2 mmol), VIMAR (2.79 g, 4.4 mmol) and YVyOK (3.78 g, 33.8 mmol). The reaction mixture is stirred under microwave irradiation at 1202C for 20 minutes. The mixture is diluted

EA (100 ml) and washed with water (3x50 ml). The organic phase is isolated, dried and concentrated to dryness. The residue is placed in diluted NaCl (pH-1, 100 ml) and the resulting mixture is extracted with USM (3x100 ml) to remove impurities. The aqueous phase is alkalized (pH-9-10) with solid Ma»2bOz and extracted with OSM (3x100 ml). The combined organic layers were dried, concentrated and purified using silica gel chromatography (EA/MEeOH-50/1) to give the title compound as a white solid (500 mg, 20 95). |LCMS: -2.09 min., t/2 439.3 (MAN) Y. c) 1-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-4-yl 4-isopropylpiperazine-1 -carboxylate

Oh ke vovi y

To a suspension of 1-(6-(benzyloxy)-pyridin-3-yl)-piperidin-4-yl 4-isopropylpiperazine-1-carboxylate (200 mg, 0.46 mmol) in MeonN (10 ml) add 10 95 Ra/ C (200 mg) and the resulting mixture is hydrogenated (hydrogen cylinder) at room temperature for 10 minutes. The catalyst is removed by filtration through celite, and the resulting filtrate is concentrated in vacuo.

The desired product is obtained as a white solid after purification by preparative HPLC (40 mg, 25 95).

HN NMR (400 MHz, Meob-a") b 7.50 (dd, 9-10 Hz, 9d2-3.2 Hz, 1H), 6.81 (d, 9-32 Hz, 1H), 6, 41 (d, 9-10 Hz, 1H), 4.68 (m, 1H), 3.45 (width 4H), 3.00 (m, 2H), 2.75 (m, ЗН), 2, 59 (m, 4H), 1.90 (m, 2H), 1.70 (m, 2H), 1.02 (d, U-6.4 Hz, 6H); RHMS: K-1.37 min., t/2 349.2. (MAN).

Table 1 shows the compounds of formula (I). Compounds of examples 1.1-1.6 are synthesized in accordance with method A; Compounds of examples 2.1-2.3 are synthesized in accordance with method B;

The compound of example 3.1 is synthesized in accordance with method b.

Table 1

RHMS

Pr. Structure Name method B | (MANI

I(min. 9 - 1-(6-oxo-1,6-dihydropyridazine- - U- -25 | Z-yl)piperidin-4-yl 4- 1 ok Ku Cl cyclobutylpiperazine-1- 1,65(А) 3622 carboxylate 1-(1-methyl-6-oxo-1,6-

He MO- dihydropyridazine-3- 12 -ora yl)piperidin-4-yl 4-1,K(A) 364.2 7 00 isopropylpiperazine-1-carboxylate - 1-(6-oxo-1,6-dihydropyridazine - 13 0-4 73-M 0-9 b Z-yl)/piperidin-4-yl 4- 1,33(A) 3502 ' MM Ku isopropylpiperazine-1- ; ; carboxylate n o A 1-(6-oxo-1,6-dihydropyridazin- -MM M M Z-yl)piperidin-4-yl 4-

Shi oo h-/ z cyclobutylpiperazine-1- 105) | 348.2 more carboxylate 1-(1-methyl-6-oxo-1,6- och dihydropyridazine-3-

OO o yl)piperidin-4-yl 4-1,4A(A) | 0.87 (A) ОЙ 378.2 - вх isopropylpiperazine-1-carboxylate 15

Continuation of table 1 about 1-(1-methyl-2-oxo-1,2- dihydropyridin-4-yl)piperidin-29ul 4-yl 4-isopropylpiperazin-1-1,91(B) 363.3 b 0- carboxylate o 1-(2-oxo-1,2-dihydropyridin-4-xyl)upiperidin-4-yl 4- 2.2 "Oz vo isopropylpiperazine-1- 1,91(B) 361.2 o carboxylate o 1 -(2-oxo-1,2-dihydropyridin-4-yl)upiperidin-4-yl 4- 2.3 "Z y isopropylpiperazin-1-theb(B) 38.2 o 0- carboxylate

Y - 1-(6-oxo-1,6-dihydropyridin-3- - M - yl)upiperidin-4-yl 4-

For 0-0 LAK o - isopropylpiperazine-1- 1.34) 49.2

H carboxylate

Biological testing 1.1 IP-migo testing

A) Evaluation of efficiency

The effectiveness of the compounds of this invention as antagonists of NZ receptors can be assessed by measuring the blockade of (K)-alpha-methylhistamine-mediated CAMP production using the GAMSE Oiga CsAMP kit (RE ZhTKEO263) in CHO cells expressing human NZ3 receptors (SepVapk: ВСО96840; Zigaizregu VI ей ай, Rgos. Mai). Asai. bare feet O.5.A. 99(26), 16899-16903; 2002).

Protocol: 1. Preparation of stimulating buffer (30 ml): 29.4 ml of NVZ5 (SBIVSO 514025), 150 μl of 1 M

NEREZ (SIVSO 515630), 30 μl of 500 mM IVMH (SAGVIOSNEM 2410957) and 400 μl of 7.5 95 VBA (aivsSo я10438-026). 2. Preparation of an analytical tablet: Different concentrations of the compounds of this invention (0.01-1000

NM), NZ positive controls and CAMP calibration standards; With mm REog5Koiip (SAGVIOSNEM 3442709); 5 µM (K)-alpha-methylhistamine (NH receptor agonist); 1 96 DMSO (5ISMA 202650); full volume: 95 nl. 3. Preparation of cell solution: Combine cells with stimulating buffer, final density: 100,000 cells/ml. 4. Reaction: (a) transfer of 10 μl of cell solution to an analytical plate, (b) centrifugation at 600 rpm. for 3 minutes, and incubating for 50 minutes at room temperature, (c) adding to the analytical tablet 5 μl of 4X Ei-cAMP indicator solution (60 μl of Ei-CAMP starting indicator solution 2.94 ml of cAMP detection buffer) and 5 μl of 4X solution OHidpEMm-anti-CAMP (20 μl of Ey-cAMP initial indicator solution 42.98 ml of CAMP detection buffer). 5. Reading data from the tablet using Ep Mysiop: flash energy: 100 95; excitation filter: 111 Ω2 320; emission filter: 203 (Ey 615) and 205 (ARS 665); number of laser flashes: 20; window 100 psec; laser mirror module: 445 or 446; laser cycle:

From 16600 μsec. 6. Analysis of results using the SgarpRide Rgizt system: dependence of the reaction on Id (concentration of the compound); adjustable tilt.

C) Assessment of kinship

The affinity of the compounds of this invention to the NZ receptor can be assessed by measuring the change in the binding of the radioligand IZN|-M-α-methylhistamine (RegkipEIIteg, Zh MET10272500C) to membranes that contain human NZ receptors (RegkipEIIteg, Zh E5-392-M400SHA; SepVapk: MM 007232.2;

ZU eyi ai, Ipiegpayopa! Opiop oi Rnaptasoiodo XII. SiIazziiisaiop oi piziatipe geseriog5, РНаптасой

Vem, 49(3), 253-278, 1997).

Protocol:

1. Preparation of the binding analytical buffer (500 ml) 25 ml of 1 M Ttgib-HCl pH 7.5 (Ipigodep, Zh 15567-027), 2.5 ml of 1 M MaoSi" (bidta, 2 M1028-100ML), 472 .5 ml of dango. 2. Serial dilutions of compounds: dilutions are carried out using ViotTek Rhesiziop on a compound dilution plate. Concentrations of compounds start with 5 or 10 µM, 10-point titration of doses with 3- or 5-fold serial dilutions.

C. Preparation of 2x membrane solution (25 ml): 1.25 ml of the original solution of human histamine NR receptors, 23.75 ml of analytical buffer. 4. Preparation of 2x solution of IZNI|-M-c-methylhistamine (25 ml): initial solution of 4.27 μl of IZNI-M-a-methylhistamine, 25 ml of analytical buffer. 5. Assembling the binding reaction: (a) transfer 1 μl of the compound solution, 1 μl of 100 95 DMSO and 1 μl of 1 M (K)(-)-α-methylhistamine (Zidta, Zh NI128) on a reaction plate at room temperature, (5) transfer of 50 μl of 2x protein solution to a reaction plate, (c) transfer of 49 μl of 2x radioligand solution to a reaction plate (SogpipdF 96-well EIA/KIA plate; zZidta, and SI 53797) b. Cover the reaction plate with TorzZeai!M-A film (Regkip EITeg, 6005185) and incubate at 282 for 120 minutes. Equilibrate the 2era 5rip desalting plates (Tpepto Zsiepiis, 2 89808) at room temperature for 120 minutes. 7. Remove the sealing material from the bottom of the filter plate Place plate on wash plate Centrifuge at 1000 rpm for 2 minutes to remove storage buffer at room temperature 8. Transfer 70 µL of reaction mixture from reaction plate to filter plates.

Filter tablets are placed on top of folding tablets. Centrifuge the assembly plates at 1000 rpm for 2 minutes to collect the protein with bound radioligand.

Add 200 μl of Misgossypi-40 (RegKipEITe!g, and 6013641-11) to each well of the assembly plate. Cover the tablets with Torzeai "m-DA" film. 9. Read the results from the tablets using UmMaiias Misgoreia Tiyih 2450, device setting parameters: pulse mode: SRM, pulse time: 2 minutes. 10. Analysis of the results: System sgarpRaai Rgiht: reaction depending on Iodine(concentrations of the compound); variable slope Ki is calculated based on the Chang and Prusoff equation: Ki -

From IChvod1 "Tsradioligand/Ka))

Table 2 presents the Ki values for the above-described evaluations of the effectiveness/affinity of the compounds of this invention in relation to human NH receptors.

Table 2

Efficiency Affinity Efficiency Affinity 23 | 6 June 09 | 12 1.2 IP-MIMO testing

A) Influence on the level of brain tele-methylhistamine

The compounds of this invention are dissolved in 20 95 2-hydroxyl-beta-cyclodextran (HVS) and briefly treated with ultrasound until there is no suspension left in the resulting solution (or there is little left). Animals (male rats of the Zrgadze-Oamleu strain at the age of 8 weeks) are administered oral doses of the test compounds in 1 hour. or other longer periods of time before they are killed using CO."

Collection of blood samples: Cardiac puncture is performed to collect blood samples from the heart cavity. Collected blood is slowly mixed with EOTA-K2 20 μl/ml to avoid blood clotting. The blood samples in the tubes are then centrifuged (15 min, 6000 rpm), and the plasma is transferred to new tubes and then temporarily stored on dry ice until stored in a freezer at -7020.

Collection of C5E: C5E samples are collected from the greater occipital foramen of animals (using a 0.5 IV needle), and the resulting C5E samples are stored on dry ice.

Selection of brain tissues: Rat brains are removed from the skull and first washed with ice-cold saline solution. The frontal lobe is isolated from the rest of the brain on ice contained in a petri dish. Determine the wet mass of the frontal part, immediately register. The frontal sample is then stored on dry ice until transferred to a freezer at -7020.

Bioanalytical methods of research of tele-methylhistamine and compounds:

Instrument: Addiepi 6410, mass spectrometer with three quadrupole lenses

Matrix: rat plasma, frontal homogenate and cerebrospinal fluid (CSF)

Analyte: NH compounds.

Internal standard: dexamethasone

HPLC conditions:

Mobile phase A: NgO-0.1 95 MNa: NgO:

Mobile phase B: meon-0.1 95 МНЗ-Н2гО

Column: Shiitaise KhV-S 18 (2.1x50 mm, 5 μm)

Flow rate: 0.45 ml/min, temperature: 4020

MS terms:

EI (electrospray ionization): positive ions

MEM (magnetic resonance microscopy) detection

Dexamethasone: (MANI-t/7 393.3--373.2; CE:4; Fragmentor:110

Obtaining a sample:

Frontal part: the brain sample is homogenized for 2 minutes with 3 volumes (v/w) of homogenization solution (EN:РВ5-85:15), and then centrifuged at 12,000 rpm. within 5 minutes. To 30 μl of brain homogenate sample supernatant, 30 μl of internal standard (dexamethasone, 300 ng/ml) is added followed by 150 μl of AFM for protein precipitation.

The mixture is rotated for 2 minutes and centrifuged at 12,000 rpm. within 5 minutes. 5 μl of the supernatant is injected into the LC-MS/MS for analysis.

Plasma and C5E: To a 30 µl aliquot of the sample, add 30 µl of internal standard (300 ng/ml dexamethasone) followed by 150 µl of AFM to precipitate the protein. The mixture is vortexed for 2 minutes and then centrifuged at 12,000 rpm. within 5 minutes. 5 μl of the supernatant is injected into the LC-MS/MS for analysis.

Table C presents the results of measurements of tele-methylhistamine levels in the brain.

Table C

Coo)

C) Effects on wakefulness

Animals: Male rats of the Zrhadne-Oamu strain (280-320 g) are used individually at an ambient temperature of 22--0.52C, relative humidity of 60-29o and with automatic control of the cycle of 12 hours of light and 12 hours of darkness (the light is turned on at 07: 00, lighting intensity - 100 lux). Animals have free access to food and water.

EES recording mode, Royudgarpis Kesogaipud5 and Midyapse ia analysis: Under anesthesia with phenobarbital (50 mg/kg, intraperitoneally), rats are implanted with EES and electromyogram (EMO) electrodes are recorded for polysomnographic recordings (Nyapo ei ai, U. Meigovzsi, 23, 5975-5983 , 2003). Two stainless steel screws (1 mm diameter) of EEO electrodes (first screw: anterior-posterior (AR), 2 mm; left-right (IR), -2 mm; and second: AR, -2 mm; I K, - 2 mm, AR from bregma, IR from lambda) and a comparison electrode (on the opposite side of the EES of the screw,

AR, 3 mm; I K, Z mm) are surgically implanted with a stainless steel screw for fixation of the skull.

Two Teflon-insulated stainless steel wires are placed bilaterally in both trapezius muscles to serve as EMO electrodes for rats. All electrodes are attached to micro-connectors and fixed on the skull with dental cement.

Registration of EES and EMO is carried out with the help of a sliding ring designed in such a way that the behavioral movement of rats is not restricted. After an 8-day recovery period, rats are housed individually in transparent cylinders and habituated to recording cables for 3-4 days prior to polygraphic recordings.

To study sleep-wake cycles, each animal is recorded for 24 hours starting at 19:00, the light-off period. Then the animals are transferred to the pharmacological phase of research, in which sleep-wake parameters are recorded for 72 hours. The data obtained during the first 24 hours also serve as a baseline of comparison data for the second day of experiments.

Cortical EES and EMO signals are amplified, filtered (EES, 0.5-30 Hz; EMO, 20-200 Hu), digitized at a sampling rate of 128 Hz, and recorded using ZI EERBISM (Kivzei

Sothies, Madapo, Darap). After the completion of the experiment, the polygraph records are automatically evaluated in the oiShipe mode at 4-second intervals as wakefulness, KEM, and MKEM sleep, using 5IEERBISM, in accordance with standard criteria (Nyapu ei ai, Mai

Meiyogossi, 8, 858-859, 2005). As a final stage, certain sleep-wake stages are examined visually and, if necessary, corrected. The EES of the specific density curve is built for each stage within 4 hours after the introduction of the medicinal product. The intensity of each position at 0.25 Hz is averaged across sleep or wake stages and normalized for the group by calculating the percentage of each position at full intensity (0.25-25 Hz).

Pharmacological treatments: Test compounds, caffeine (positive comparative compound) or compounds of this invention are prepared as a 20 95 solution of 2-hydroxyl-beta-cyclodextran (HBO). On the day of vehicle treatment, all animals are injected with vehicle at 9:00 am. On the day of drug treatment, the test compound, caffeine, or vehicle is administered at 9:00 a.m. After introduction, continuous records are kept for 3 days. Volumes are administered orally or intraperitoneally at a dose of 2 ml/kg. Separate groups of rats are used for each dose (n-8 rats in a group).

Changes over time in the amount of sleep-wake, the number of sleep-wake transitions, as well as the number and duration of sleep/wake periods in the light/dark phases are analyzed using a paired i-test, with each animal serving as its own control.

Table 4 represents the results of measurements of the percentage of increase in wakefulness in rats.

Results are presented for the first 4 hours after oral administration of the compounds.

Table 4 хр«0.5, и ре0.01 (comparison with the carrier group)

In one embodiment, the present invention provides a method of inhibiting NR receptors in a subject, wherein said method includes administering to said subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method of treating a disorder or disease mediated by NO receptors in a subject, wherein said method comprises administering to said subject a therapeutically effective amount of a compound of the formula | or her

From a pharmaceutically acceptable salt. Preferably, said disorder or disease is selected from narcolepsy; fatigue associated with multiple sclerosis; fatigue associated with Parkinson's disease; cognitive impairment associated with schizophrenia; cognitive impairment associated with Alzheimer's disease; moderate cognitive impairment; Tourette syndrome; and attention deficit hyperactivity disorder; and especially narcolepsy.

In another embodiment, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of a disorder or disease mediated by NH receptors in a subject.

In another embodiment, the present invention provides the use of a compound of the formula or a pharmaceutically acceptable salt thereof for the treatment of a disorder or disease in a subject characterized by abnormal activity of NZ receptors. Preferably, if the specified disorder or specified disease is selected from narcolepsy; fatigue associated with multiple sclerosis; fatigue associated with Parkinson's disease; cognitive impairment associated with schizophrenia; impairment of cognitive functions associated with the disease

Alzheimer's; moderate cognitive impairment; Tourette syndrome; and attention deficit hyperactivity disorder; and especially narcolepsy.

In yet another variant, the present invention proposes the use of a compound of the formula or a pharmaceutically acceptable salt thereof for the treatment of a subject in a disorder or disease associated with a violation of the transmission of a receptor-modulated signal.

Preferably, if the specified disorder or specified disease is selected from narcolepsy; fatigue associated with multiple sclerosis; fatigue associated with Parkinson's disease; cognitive impairment associated with schizophrenia; cognitive impairment associated with Alzheimer's disease; moderate cognitive impairment; Tourette syndrome; and attention deficit hyperactivity disorder; and especially narcolepsy.

II. Solid forms of carbamate derivatives

This invention also relates to solid forms of 1-(1-methyl-b-oxo-1,6-dihydropyridazine-

Z-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate and to pharmaceutical compositions containing them and to their use as medicinal products.

Compound 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate of formula 1A

In ko x- -5 / Ku (A); disclosed above.

Selection criteria for solid forms depend on the intended indication and route(s) of administration. For CNeO indications, such as narcolepsy, with an intended oral route of administration, it is important, for example, to ensure good absorption/oral bioavailability. It is especially effective if the solid forms are crystalline forms characterized by low hygroscopicity, good solubility in water, high melting point and which do not exist in multiple forms (for example, in the forms of polymorphs, solvates and/or hydrates). Other important parameters are safety aspects (eg, low toxicity), volumetric stability, compatibility with excipients, pH of aqueous solutions, good morphology, and ease of processing.

The present invention offers a free form of 1-(1-methyl-6b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in solid form. In addition, the present invention proposes a salt of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in solid form, where the specified salt is Citrate, hydrochloride, fumarate, adipate, maleate or sebacate of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate. Unless otherwise indicated, the indicated free form or the indicated salt are collectively referred to herein and hereinafter as """VERDA

FORM OF THIS INVENTION".

As used herein, the term "solid form" may include hydrates and

To solve

As used herein, the term "crystalline form" refers to a solid form of a molecule, atom, and/or ion in which its constituent atoms, molecules, and/or ions are arranged in an ordered manner that repeats the spatial pattern in all three dimensions.

As used herein, the term "polymorph" refers to crystalline forms that have the same chemical composition but differ in the spatial arrangement of the molecules, atoms, and/or ions that make up the crystal.

As used herein, the term "amorphous form" refers to a solid form of a molecule, atom, and/or ion that is not crystalline. Amorphous solids do not show a specific X-ray diffraction pattern.

As used herein, the term "solvate" refers to a form, e.g., a crystalline form, of molecules, atoms, and/or ions that further include solvent or solvent molecules incorporated into the structure of a solid, e.g., a crystal lattice structure. The solvent molecules in the solvate may be present in a regular arrangement and/or in a random arrangement. These solvates may include either stoichiometric or non-stoichiometric amounts of solvent molecules. For example, a solvate with a non-stoichiometric number of solvent molecules can form as a result of partial loss of solvent from the solvate. Solvates can exist as dimers or oligomers containing more than one molecule of 1-(1-methyl-6-oxo-1,b-dihydropyridazin-3-yl)piperidin-4-yl. /- 4-cyclobutylpiperazine-1-carboxylate inside the crystal lattice structure.

As used herein, the term "substantially pure" when used in reference to solid form means a compound, for example, a salt (such as 1-(1-methyl-6-oxo-1,6-dihydropyridazine-3 -yl)ipiperidin-4-yl.4-cyclobutylpiperazine-1-carboxylate), with a degree of purity of more than 90 wt. 95, including values greater than 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99 wt. 95, and also including values up to about 100 wt. 95 compounds, for example, citrate 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazin-1-

carboxylate, based on the mass of the solid form. The rest of the material in the specified solid form may include, for example, reaction impurities and/or processing impurities resulting from its preparation and/or - if possible - another form(s) of the compound. For example, the crystalline form of 1-(1-methyl-6b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate citrate can be considered practically pure if its degree of purity is more than 90 wt. 96, when measured by methods that are currently known and recognized by specialists in the field, thus the rest is less than 10 wt. 95 material includes reaction impurities and/or processing impurities.

As used herein, the term "mono-" in connection with acids refers to a base to acid ratio of about 1:11. As used herein, the term "sesqui-" in connection with acids refers to a base to acid ratio of about 1:1.5.

As used herein, the term "di-" in connection with acids refers to a base to acid ratio of about 1:2.

The term "substantially the same" in relation to the positions of the peaks of the X-ray diffraction pattern means that the variability of the typical positions and intensities of the peaks is taken into account. For example, those skilled in the art will appreciate that the peak positions of (29) may exhibit some instrument-related variability, typically on the order of 0.22. Additionally, as will be appreciated by those skilled in the art, peak intensities may exhibit some instrument-related variability as well as variability related to degree of crystallinity, preferred orientation, sample surface preparation, and other factors well known to those skilled in the art. , and should be considered only as qualitative values. 1. Free form

In one embodiment, the solid form of this invention is the free form of 1-(1-methyl-6b-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate, for example, in crystalline form 1.1. The first free form option:

The free form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form (form A of the free form) can be

Zo is obtained as a result of crystallization by cooling a supersaturated solution of the compound in ethyl acetate at concentrations of about 100 mg/ml. The transparency temperature (the temperature at which the compound dissolves) is about 352C. The cloud point (the temperature at which the compound crystallizes) is about 42C. The HAERO pattern of the sample obtained in this way (see also example 1I.1.1) is presented in FIG. AND. Measurements are carried out at a temperature of about 222C and at a wavelength of X-ray radiation /, 1.5418A (SiKa

A-1.54185A). diagram of KhKRO zhi a 00091 du grad. (imp) degree (imp) 6 | 160 | 3079 zh"yR 8 | 173 | 71215 9 | 181 | 1995 2Zh E 22 | 30 | sh(x699' g

In one embodiment, Form A of the free form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form is characterized by a HCRO pattern containing at least four, more preferably five, most preferably all the following peaks at reflection angles 2 theta (29) 4.9, 15.4, 16.9, 20.5, 20.8 and 24.4, 0.2, respectively .

Zo

In one variant, Form A of the free form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in its crystalline form is characterized by a HCRO pattern almost the same, as well as the picture of KhKRO presented in FIG. 1A.

Form A of the free form shows good solubility in an aqueous environment in the pH range of about 1-8. Its melting point is determined by heating at a rate of 102C/minute, which is about 12320. 1.2. The second variant of the free form:

The free form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form (form B of the free form) is disclosed in the examples section ( see example 1I.1.2). The corresponding picture of ХКРО is presented in FIG. 18. diagram of KhKRO zhi a 00091 du | in the city (imp) degree (imp) 6 | 167 | (2577. Zh S 8 | 183 | 738.2 sh 9 | yuyu shyu186 | 802 g ChHCX

In one embodiment, Form B of the free form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form is characterized by a XERO pattern containing at least four, more preferably five, most preferably all the following peaks at reflection angles 2 theta (29) 9.4, 11.3, 13.6, 15.0, 16.0, 16.7, 17.4, 18 ,3, 18.6, 19.4, 20.8, 21.7, 22.7, 23.2, 24.0, 24.6, 27.7, 27.8, 28.1, 28.7 , 29.5, 29.9, 31.6, 32.5, 32.7, 33.5, 33.6, 34.3, 35.1, 35.6, 36.1, 37.0, 37 .7 and 39.2, 0.2, respectively.

In one embodiment, Form B of the free form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form is characterized by a HCRO pattern containing at least four, more preferably five, most preferably all the following peaks at reflection angles 2 theta (29) 9.4, 19.4, 22.7, 23.2, 27.7 and 27.8, -0.2, in accordance.

In one embodiment, Form B of the free form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form is characterized by a HCRO pattern almost the same, as well as the picture of KhKRO presented in FIG. 18.

Form B in free form shows good solubility in an aqueous environment. Its melting point is determined by heating at a rate of 102C/minute, which is about 1242C (onset).

Salts 2. Citrate salt:

In one embodiment, the solid form of this invention is the citrate salt of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate, for example, in crystalline form 2.1. The first option of citrate salt:

The citrate salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form (form A of the citrate salt) can be obtained from a mixture of acetone /diethyl ether, if two equivalents of citric acid are used.

The compound shows good solubility in an aqueous environment. Its melting point is determined by heating at a rate of 102C/minute as about 141.220.

The X-ray powder diffraction pattern (XDR) of the sample obtained by the specified method (see also example 1I.2.1) is presented in FIG. 2A. Measurements are carried out at a temperature of about 222C and at a wavelength of X-ray radiation, АХ, 1.5418А (СиКА А-1.54184А). diagram of the KhKRO scha 0 bo || a (grad.o (imp) (grad.? (imp) 12 1 182 1777777717199 2 2sh « 6 | 173 | (01222 16 1 sh«B4 YUBYIZH 60 g 8 1 208 2 sh | po z KE" 9 | yuyu yuschyusch2g56 | 108

In one embodiment, Form A of the citrate salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form is characterized by a HCRO pattern containing at least four, more preferably five, most preferably all the following peaks at reflection angles 2 theta (29) 14.0, 16.6, 17.3, 17.5, 19.4 and 24.0 -0.2, respectively .

In one variant, form A of the citrate salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in the crystalline form is characterized by an ХКРО pattern almost the same, as well as the picture of KhKRO presented in FIG. 2A.

According to the analysis of the proton NMR spectrum of the salt of example 1.2.1 (see FIG. 28B), the base/acid ratio is about 1:1.5.

In one embodiment, the solid form of this invention is the sesquicitrate salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutyl-piperazine-1-carboxylate.

In one variant, the solid form of this invention is the sesquicitrate salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutyl-piperazine-1-carboxylate in a crystalline form 2.2. The second option of citrate salt:

Citrate salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form (Form B of citrate salt) can be obtained from acetone, if one equivalent of citric acid is used.

The compound shows good solubility in an aqueous environment. Its melting point is determined by heating at a rate of 102C/minute, as about 17226.

The X-ray diffraction (XRD) pattern of the sample obtained by the specified method (see also example 1I.2.2) is presented in FIG. 2C. This sample contains about 1.5 95 residual acetone. Measurements are carried out at a temperature of about 222C and at the wavelength of X-rays A, 1.5418A (SiKa A-1.54184). diagram of the KhKRO same state 00091 du | in (grad.? (imp) (grad.? (imp) 6 | 127 | 134 20 | 267 | 98 8 | 52 | (hm s continuation of the KHARO diagram 9 | 163 | 81 5 skh kchmU 25 | 349 | 6

In one embodiment, Form B of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate citrate salt in crystalline form is characterized by a XERO pattern that contains at least four, more preferably five, most preferably all the following peaks at reflection angles 2 theta (29) 3.2, 9.3, 10.8, 12.0, 15.1, 16.3, 16.4, 17 ,3, 18.3, 18.6, 19.3, 20.7, 23.3 and 23.9, 0.2, respectively.

In one variant, form B of the citrate salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in the crystalline form is characterized by an ХКРО pattern practically the same, as well as the picture of KhKRO presented in FIG. 2C. 3. Hydrochloride salt:

In one variant, the solid form of this invention is the hydrochloride salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)ipiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate, for example, in crystalline form . 4.1. The first version of the hydrochloride salt:

The hydrochloride salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form (form A of the hydrochloride salt) can be obtained from acetone if use one equivalent of hydrochloric acid.

The compound shows good solubility in an aqueous environment. Its melting point is determined by heating at a rate of 102C/minute as 249.2C (onset) with the following schedule. The XKRO picture of the sample obtained by the specified method (see also example 1I.3.1) is presented in FIG. BY. Measurements are carried out at a temperature of about 222C and at the wavelength of X-ray radiation, A 1.54184A (SiKa A-1.54184A). diagram of KhKRO Oct | mu 000 | du | in the city (imp) degree (imp) 12 | 364 | 68 13 | 390 | 66 6 | 1772 | 96 8 220 | 9 9 HER 7190 | ShKhu828

In one embodiment, Form A of the hydrochloride salt of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form is characterized by a HCRO pattern that contains at least four, more preferably five, most preferably all of the following peaks at reflection angles of 2 theta (29): 16.4, 17.2, 20.2, 242, 27.5 and 29.750.2, respectively.

In one variant, form A of the hydrochloride salt of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in its crystalline form is characterized by a ХКРО pattern practically the same, as well as the picture of KhKRO presented in FIG. BY. 4.2. The second version of the hydrochloride salt:

The anhydrous hydrochloride salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form (Form B of the hydrochloride salt) can be obtained from acetone, if two equivalents of hydrochloric acid are used.

Salt shows good solubility in water. Its melting point for a sample stored at 402C and 75 95 relative humidity for 7 days is determined by heating at a rate of 102C/minute to be about 2502C (set).

The X-ray diffraction (XRD) pattern of the sample obtained by the specified method (see also example 11.3.2) is presented in FIG. ZV. Measurements are carried out at a temperature of about 222C and at the wavelength of X-ray radiation, A 1.54184A (SiKa

A-1.54185A). diagram of KhKRO same state (grad.? (imp) (grad.? (imp) 111 57 | 98 g 6 | 133 | 48 8 | 154 | (lyu 111 24177711 270. 17р7р7р7р1р1с19661 9 | щющ159 | 970 ж 16 | 200 | 80 (YAVvSh

In one embodiment, Form B of the hydrochloride salt of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form is characterized by a HCRO pattern that contains at least four, more preferably five, most preferably all of the following peaks at reflection angles 2 theta (29): 5.7, 9.1, 10.0, 10.7, 11.9, 13.3, 13.7, 15.4, 15.9, 16.5, 16.8, 17.1, 18.3, 18.7, 19.5, 20.0, 20.7, 23.6, 24.2, 25, 0, 25.4, 26.9, 27.0, 27.7, 29.4, 30.1, 31.9, and 32.7:50.2, respectively.

In one variant, form B of the hydrochloride salt of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in its crystalline form is characterized by a HCRO pattern almost the same, as well as the picture of KhKRO presented in FIG. ZV. 4. Fumaric acid salt:

In one variant, the solid form of this invention is the fumarate salt of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate, for example, in crystalline form . 3.1. The first version of the fumarate salt:

The anhydrous fumarate salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form (form A of the fumarate salt) can be obtained from a mixture methanol/acetone according to the method of example 4.1, if one equivalent of fumaric acid is used.

Salt shows good solubility in water. Its melting point is determined by heating at a rate of 102C/minute, as about 15620.

The X-ray diffraction (XRD) pattern of the sample obtained by the specified method (see also example 11.4.1) is presented in FIG. 4A. Measurements are carried out at a temperature of about 222C and at the wavelength of X-ray radiation, A 1.54184A (SiKa

A-1.54185A).

diagram of KhKRO zhi shcha 0091 du (grad.? (imp) (grad.? (imp) 6 | 139 | 661 7 | 160 | sh9 8 | 1607 | --(KMGHLl7a28 9 | 1682 YuSh(| 1725 30 | 337 | 80 Mr

In one embodiment, form A of the fumarate salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form is characterized by a XERO pattern containing at least four, more preferably five, most preferably all of the following peaks at reflection angles 2 theta (29): 6.5, 10.1, 10.7, 12.4, 13.0, 13.9, 16.7, 16.8, 17.2, 17.7, 18.8, 20.2, 20.5, 21.6, 21.9, 22.1, 23.1, 23.4, 25.0, 25.1, 25.4, 26.4, 27.5, 28.0, 28.8, 29.9, 32.8 and 33.20.2, respectively.

In one variant, form A of the fumarate salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in its crystalline form is characterized by a HCRO pattern almost the same, as well as the picture of KhKRO presented in FIG. 4A. 3.2. The second version of the fumarate salt:

The anhydrous fumarate salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form (form B of the fumarate salt) can be obtained from a mixture methanol/acetone according to the method of example 4.2, if two equivalents of fumaric acid are used.

Salt shows good solubility in water. Its melting point is determined by heating at a rate of 102C/minute, as about 15520.

The X-ray diffraction (XRD) pattern of the sample obtained by the specified method (see also example II. 4.2) is presented in FIG. 48. Measurements are carried out at a temperature of about 222C and at a wavelength of X-ray radiation A of 1.5418A (SiKa

A-1.54185A). chart of KhKRO zhi shcha 00091 du | in the city (imp) degree (imp) 27. | 228 | 6698 6 | 18 | 72 8 | 13 | 7178 9 | yushyush138 | 1953 shZh g | 2 | (R 699...

zhi a mu 00091 du | his city (imp) degree (imp) 45 | 347 | 98

In one embodiment, form B of the fumarate salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form is characterized by a ХКРО pattern containing at least four, more preferably five, most preferably all of the following peaks at reflection angles of 2 theta (29): 6.4, 8.7, 10.6, 11.3, 11.8, 12.9, 13.8, 14.0, 15.7, 16.2, 16.6, 16.9, 18.7, 18.8, 19.1, 19.3, 19.7, 20.5, 21.0, 21, 4, 21.9, 22.68, 23.8, 24.0, 24.4, 24.7, 25.2, 25.6, 26.0, 26.1, 27.8, 29.1, 29.5, 30.6, 31.4, 321, 32.7, and 35.3:-0.2, respectively.

In one variant, form B of the fumarate salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in its crystalline form is characterized by a HCRO pattern almost the same, as well as the picture of KhKRO presented in FIG. 48.

Methods of obtaining crystalline forms

Crystalline forms can be obtained in a variety of ways, including, for example, crystallization or recrystallization from a suitable solvent, sublimation, melt growth, solidification from another phase, crystallization from a supercritical fluid, and atomization from a nozzle. Techniques for crystallization or recrystallization of crystalline forms from a mixture of solvents include, for example, evaporation of the solvent, lowering the temperature of the solvent mixture, introducing seed crystals into a supersaturated mixture of solvent molecules and/or salt, freeze-drying the solvent mixture, and adding antisolvents (antisolvents) to the solvent mixture. High yields of crystallization techniques can be used to obtain crystalline forms, including polymorphs.

Medicinal crystals, including polymorphs, methods of preparation, and characterization of medicinal crystals are discussed in Zoiia-eiai6e Spetiwig oi Ogide, 5.8. Vut, V.V.

Rieineg, apa 9.sh. etoueiY, 2pa Ediiop, 5501, Mewi I atauetsne, Ipaiapa (1999).

For crystallization techniques that use a solvent, the choice of solvent or solvents usually depends on one or more factors, such as the solubility of the compound, the crystallization technique, and the vapor pressure of the solvent. Combinations of solvents can be used, for example, a compound can be solubilized in a first solvent to give a solution, followed by the addition of an anti-solvent to reduce the solubility of the compound in the solution and form crystals. An antisolvent is a solvent in which the specified compound has

Because of low solubility.

In one method of obtaining crystals, the compound is suspended and/or stirred in a suitable solvent to form a suspension that can be heated to promote dissolution. The term "suspension", as used herein, means a saturated solution of a compound, which may also contain an additional amount of the compound, obtaining a heterogeneous mixture of the compound and the solvent at a given temperature.

Seed crystals can be added to any crystallization mixture to promote crystallization (see "Rgodgattei Sooiipdo oi Vaisp StiziaiPi?egv", 9U.M/.Miiiyp apa 9. Mumii, Spetisai

Epaipeegipud Zsiepse, 1971, 26, 369-377). Small seed crystals are usually used. Seed crystals of small size can be obtained as a result of sieving, grinding or micronization of large crystals, or by microcrystallization of solutions. Precautions should be taken so that the grinding or micronization of the crystals does not result in any changes in the crystallinity of the desired crystal forms (ie, changes to an amorphous form or to another polymorph).

The cooled crystallization mixture can be vacuum filtered and the separated solids can be washed with a suitable solvent, such as a cold recrystallization solvent,

and dried in a stream of nitrogen, obtaining the desired crystalline form. The isolated solids can be analyzed using suitable spectroscopic or analytical techniques such as solid-state nuclear magnetic resonance, differential scanning calorimetry, X-ray powder diffraction, or the like, to confirm the formation of the predominant crystalline form of the product. The obtained crystalline form is usually obtained in an amount of more than about 70 wt. from the selected output, preferably, more than 90 wt. 95 of the selected yield, based on the initial mass of the compounds used in the crystallization procedure. The resulting product can be passed through a sieve or passed through a sieve under pressure to break up lumps, if desired.

Crystalline forms can be obtained directly from the reaction medium of the final process of obtaining 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or the solid form of this invention . This can be achieved, for example, by using at the final stage of the process a solvent or a mixture of solvents from which the solid form of this invention can be crystallized. Alternatively, crystalline forms can be obtained by distillation or by solvent addition.

Solvents suitable for this purpose include, for example, non-polar solvents and polar solvents, including protonated polar solvents such as alcohols and aprotic polar solvents such as ketones.

The presence of more than one polymorph in a sample can be determined by methods such as X-ray powder diffraction (XRD) or solid-state nuclear magnetic resonance spectroscopy. For example, the presence of additional peaks when comparing the experimentally obtained HCCO pattern with the simulated HCCO pattern may indicate the presence of more than one polymorph in the sample. The simulated RHCO can be calculated from the fluoroscopic data of a single crystal; see Ztiy, O.K., "A EOKTKAM Rgodgat og SaIsshaepd

Kh-Vau Romaeeg Oiitasiyup Rayegp5, " | amtepse Vadiayop I arogaiyogu, I immenptoge, SaiIiyogpia, OSVI - 7196 (Arii 1963).

One variant of this invention is a method of obtaining the citrate salt of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form, which includes the stages

Zo (a) preparation of a solution of /1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl /-4-cyclobutylpiperazine-1-carboxylate and citric acid in acetone, where the ratio 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl. 4-cyclobutylpiperazine-1-carboxylate:citric acid is about 1:2; (B) adding to the solution of stage (a) an ether antisolvent, for example, diethyl ether, until the acetone:ether antisolvent volume ratio reaches values of 1:1 to 1:5, for example, about 1:3; and (c) separation of the solid part by filtration to obtain the citrate salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl. 4-cyclobutylpiperazine-1-carboxylate in crystalline form.

One variant of this invention is a method of obtaining the hydrochloride salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl. 4-cyclobutylpiperazine-1-carboxylate in crystalline form, which includes stages (a) of obtaining a solution of /1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl /-4- cyclobutylpiperazine-1-carboxylate in acetone; (p) adding hydrochloric acid to the solution of step (a) until the ratio of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazin-1- carboxylate:hydrochloric acid will not reach values of about 1:1; and (c) isolation of the solid part by filtration to obtain the hydrochloride salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl. 4-cyclobutylpiperazine-1-carboxylate in crystalline form.

Analysis of solid forms

A solid form of the SOLID FORMS OF THE INVENTION can be characterized using various techniques well known to those skilled in the art.

These forms can be characterized and distinguished using single crystal X-ray diffraction, which is based on measurements of the unit cell of a single crystal form at a fixed analytical temperature. A detailed description of the elementary cell is presented in Ziotka 8. depzep, Kh-VKau bigisiige Oeieptipaiiop: A Rgasiisa

Syside, Mastaiap So., Mem Moik (1968), Sparieg 3. Alternatively, the unique spatial organization of atoms within the crystal lattice can be characterized in accordance with the observed atomic coordinates. Another method of characterizing the crystal structure is X-ray powder diffraction analysis, in which the diffraction pattern is compared with a simulated pattern representing pure powder material, with both patterns obtained at the same analytical temperature, and measurements of the shape under consideration are represented as of a series of 29 values (usually four or more).

Another way to characterize the specified form can be the use of solid-state nuclear magnetic resonance (NMR), differential scanning calorimetry, thermography, and a careful study of crystalline or amorphous morphology. These parameters can also be used in combination to characterize the shape under consideration.

Additional aspects

This invention also relates to the SOLID FORM OF THIS INVENTION (for example, Form A of the free form of /1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl /-4-cyclobutylpiperazine-1 -carboxylate in crystalline form) for use as a medicine.

In another embodiment, this invention relates to a SOLID FORM OF THIS INVENTION (for example, Form A of the free form of 1-(1-methyl-6b-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazin-1- carboxylate in crystalline form) for treating a disorder or disease mediated by NZ receptors in a subject. Preferably, the specified disorder or specified disease is selected from narcolepsy; fatigue associated with multiple sclerosis; fatigue associated with Parkinson's disease; cognitive impairment associated with schizophrenia; impairment of cognitive functions associated with the disease

Alzheimer's; moderate cognitive impairment; Tourette syndrome; and attention deficit hyperactivity disorder; and especially narcolepsy.

In another variant, this invention also applies to the use of SOLID FORM

OF THIS INVENTION (for example, form A of the free form of /1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl. 4-cyclobutylpiperazine-i-carboxylate in crystalline form) for the manufacture a medicinal product for the prevention, treatment and/or retardation of the subject's development of a disorder or disease mediated by NZ receptors.

Preferably, said disorder or disease is selected from narcolepsy; fatigue associated with multiple sclerosis; fatigue associated with the disease

Parkinson's; cognitive impairment associated with schizophrenia; cognitive impairment associated with Alzheimer's disease; moderate cognitive impairment; syndrome

Tourette's; and attention deficit hyperactivity disorder; and especially narcolepsy.

In another variant, this invention also applies to the use of SOLID FORM

OF THIS INVENTION (for example, form A of the free form of /1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl. 4-cyclobutylpiperazine-i-carboxylate in crystalline form) for prevention , treating and/or slowing the development in a subject of a disorder or disease mediated by NZ receptors. Preferably, said disorder or said disease is selected from narcolepsy; fatigue associated with multiple sclerosis; fatigue associated with Parkinson's disease; cognitive impairment associated with schizophrenia; cognitive impairment associated with Alzheimer's disease; moderate cognitive impairment; Tourette syndrome; and attention deficit hyperactivity disorder; and especially narcolepsy.

In another embodiment, the present invention also relates to a method of preventing, treating, and/or slowing the development of a disorder or disease mediated by NZ receptors in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a SOLID FORM OF THIS INVENTION (e.g., forms

And the free form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form). Preferably, the specified disorder or specified disease is selected from narcolepsy; fatigue associated with multiple sclerosis; fatigue associated with Parkinson's disease; cognitive impairment associated with schizophrenia; cognitive impairment associated with Alzheimer's disease; moderate cognitive impairment; Tourette syndrome; and attention deficit hyperactivity disorder; and especially narcolepsy.

In another embodiment, the present invention relates to a method of preventing, treating and/or slowing the development of a disorder or disease mediated by NZ receptors in a subject in need thereof, which comprises (i) diagnosing said disorder or disease in said subject and ( her) administration to the indicated subject of a therapeutically effective amount of the SOLID FORM OF THIS INVENTION (for example, Form A of the free form of /1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-ylpiperidin-4-yl 4-cyclobutylpiperazine -1-

carboxylate in crystalline form). Preferably, said disorder or disease is selected from narcolepsy; fatigue associated with multiple sclerosis; fatigue associated with Parkinson's disease; cognitive impairment associated with schizophrenia; cognitive impairment associated with Alzheimer's disease; moderate cognitive impairment; Tourette syndrome; and attention deficit hyperactivity disorder; and especially narcolepsy.

Amorphous forms/crystalline forms of the SOLID FORMS OF THIS INVENTION can be used as intermediate compounds to obtain crystalline forms/other crystalline forms

SOLID FORMS OF THIS INVENTION, which can be used in the treatment of the diseases/conditions listed above.

The SOLID FORM OF THE PRESENT INVENTION may be used alone or in combination or in a composition with one or more of the excipients and/or other active pharmaceutical ingredients for the preparation of medicaments as disclosed above suitable for the treatment of the above diseases/conditions.

This invention therefore also relates to pharmaceutical compositions that include

A SOLID FORM OF THE INVENTION as an active ingredient and at least one pharmaceutically acceptable carrier.

Abbreviation:

OrZS Differential scanning calorimetry

EBA analysis of the extracted gas

TOA thermogravimetric analysis

XERO powder diffraction of X-rays

Example 1.1.1: Obtaining the free form of /1-(1-methyl-6b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form

The free form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate is dissolved in ethyl acetate at a concentration of 100 mg/ml when heated to its temperature transparency at 352C. As a result of cooling to the clouding point of the compound at 42C, a crystalline product is obtained. The resulting product is analyzed using HCR (see FIG. 1A).

Example 1.1.2. Obtaining the free form of /1-(1-methyl-6b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form

In an ampoule equipped with a magnetic stirrer, 1 equivalent of each of the bases listed in the following table is dissolved in 3 ml of water. 50 mg of free form 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate together with 2 ml of methanol are added to the obtained solution. The mixture is stirred at room temperature until a clear solution is obtained. Then the stirrer is removed, and the resulting solution is left to evaporate at room temperature. After 17-24 days (see the table below), a crystalline product is obtained. The evaporation time and the amount of products obtained are listed below:

Sediments are collected and analyzed using HCRO. A typical spectrum of XeRO is presented in FIG. 18B.

Example 1.2.1: Preparation of citrate salt of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form 2 g of free form // 1-(1-Methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl/-4-cyclobutylpiperazine-1-carboxylate was dissolved in acetone (5 mL) with stirring at room temperature, and 2 .04 g (2 equivalents) of citric acid is also dissolved in acetone (5 ml) under the same conditions. Two solutions are added to a 100 ml crystallizer equipped with a magnetic stirrer and a refrigerator and mixed. After half an hour, add 30 ml of diethyl ether to the crystallizer. The suspension was filtered, and the light yellow solid was dried under vacuum at 402C for 24 hours (yield: 82.28 95). The resulting product is analyzed using XCR (see FIG. 2A) and proton NMR (see FIG. 2B). Analysis of the proton NMR spectrum indicates a base/acid ratio of about 1:1.5.

Example 1.2.2: Preparation of the citrate salt of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form 25.58 mg of citric acid dissolve in 3 ml of acetone with stirring until complete dissolution. 50 mg of the free form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate is added to the obtained solution, and the mixture is stirred at room temperature for 24 hours The resulting precipitate was collected using vacuum filtration, washed with diethyl ether, dried under vacuum at 502C for 14 hours and analyzed using HCRO (see FIG. 28), TOA/ESA and 056.

Example 1I.3.1: Preparation of the hydrochloride salt of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form

In a 100 ml crystallizer equipped with a magnetic stirrer and a refrigerator, 2 g of free form 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazin-1- carboxylate with stirring. At room temperature, 438 μl (1 equivalent) of hydrochloric acid is added dropwise. A light yellow precipitate immediately formed, and the mixture was stirred at room temperature for 3 hours. The resulting solid was filtered, dried under vacuum at 402C for 24 hours (yield: 81.5 95) and analyzed using HCR (see FIG. 3A).

Example 1I.3.2: Preparation of the hydrochloride salt of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form 50 mg of free form/1 -(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl /-4-cyclobutylpiperazine-1-carboxylate is dissolved in 3 ml of acetone. At room temperature, 22 μl of 3795 hydrochloric acid is added, and the mixture is stirred at room temperature for 24 hours. The resulting precipitate is removed under vacuum, washed with diethyl ether, dried under vacuum at 502C for 24 hours, and analyzed using HCR (see FIG. 3B), TSA/ESA and OS.

Example 1I.4.1: Preparation of the fumarate salt of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form

15.46 mg of fumaric acid is dissolved in 1 ml of methanol with stirring until complete dissolution. 50 mg of the free form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate is added to the resulting solution, and the mixture is stirred at room temperature until complete dissolution. Solvents are evaporated at room temperature for 48 hours and a yellow oil is obtained. 1 ml of acetone is added, and the mixture is stirred at room temperature for 2 hours. The yellow precipitate was removed in vacuo, washed with diethyl ether, dried in vacuo at 502C for 1 hour, and analyzed using HCR (see FIG. 4A), TOA/ESA, and O5C.

Example 11I.4.2: Preparation of the fumarate salt of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form 30.91 mg of fumaric acid dissolve in 2 ml of methanol with stirring until complete dissolution. 50 mg of the free form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate is added to the resulting solution, and the mixture is stirred at room temperature until complete dissolution. Solvents are evaporated at room temperature for 3 days and a yellow oil is obtained. Add 1 ml of acetone and stir the mixture at room temperature for 2 hours. The yellow precipitate was removed in vacuo, washed with diethyl ether, dried in vacuo at 502C for 14 hours, and analyzed using HCR (see FIG. 4A), TOA/ESA, and O5C.

In addition, the following variants of this invention are presented below:

Option 1: Free form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-i-carboxylate in solid form; or a salt of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in solid form, where this salt is citrate, hydrochloride, fumarate, adipate, maleate or sebacate of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate.

Option 2: Free form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in solid form.

Option 3: Free form in accordance with option 2, where the free form exists in crystalline form.

Option 4: Free form in accordance with option 3, where the specified free form is characterized by a picture of ХКРО practically the same as the pattern of ХКРО presented in FIG. (510) TA.

Option 5: Said free form according to any one of options 2-4, wherein said free form exists in substantially pure form.

Option 6: The free form in accordance with any one of options 2-4, where said free form has a degree of purity greater than 90 wt. 95.

Option t: Salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in solid form, where the indicated salt is citrate, hydrochloride, fumarate, adipate, maleate or sebacate of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate.

Option 8: A salt according to option 7, where said salt is 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl citrate. 4-cyclobutylpiperazine-1-carboxylate in crystalline form.

Option 9: Salt in accordance with option 8, where said salt is characterized by a picture

HERO is almost the same as the picture of ХКРО presented in FIG. 2A.

Option 10: A salt according to any one of options 7-9, wherein said salt is in substantially pure form.

Option 11: The salt according to any one of options 7-9, where said salt has a degree of purity greater than 90 wt. 95.

Option 12: A pharmaceutical composition comprising a free form as defined in any one of options 2-6 as an active ingredient and at least one pharmaceutically acceptable carrier.

Option 13: A pharmaceutical composition comprising a salt as defined in any one of options 7-11 as an active ingredient and at least one pharmaceutically acceptable carrier.

Option 14: The method of obtaining the citrate salt of 1-(1-methyl-6b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl. 4-cyclobutylpiperazine-1-carboxylate in crystalline form, which includes stages (a) of obtaining a solution of /1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl /-4- of cyclobutylpiperazine-1-carboxylate and citric acid in acetone, where the ratio of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl. 4-cyclobutylpiperazine-1-carboxylate:citric acid is about 1:2;

Zo (B) adding to the solution of stage (a) an ether antisolvent, for example, diethyl ether, until the volume ratio of acetone:ether antisolvent reaches values of 1:1-1:5; and (c) separation of the solid part by filtration to obtain the citrate salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl. 4-cyclobutylpiperazine-1-carboxylate in crystalline form.

Option 15: The method of obtaining the hydrochloride salt of 1-(1-methyl-6b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl. 4-cyclobutylpiperazine-1-carboxylate in crystalline form, which includes stages (a) of obtaining a solution of /1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl /-4- cyclobutylpiperazine-1-carboxylate in acetone; (p) adding hydrochloric acid to the solution of step (a) until the ratio of 1-(1-methyl-b-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazin-1- carboxylate:hydrochloric acid does not reach a value of about 1:1; and (c) isolation of the solid part by filtration to obtain the hydrochloride salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl. 4-cyclobutylpiperazine-1-carboxylate in crystalline form.

Brief description of the drawings

Fi. 1A shows the HCR pattern for Form A of the free form of 1-(1-methyl-6b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl. 4-cyclobutylpiperazine-I-carboxylate. 2-theta reflection angles are plotted along the X-axis, where the scale scale corresponds to 2.5 2-theta, and where the first mark on the scale corresponds to 5.0 2-theta. On the Y-axis are plotted intensities (number of pulses), where the scale scale corresponds to 2500 pulses, and where the first mark on the scale corresponds to 2500 pulses.

Fi. 1B shows the HCR pattern for Form B of the free form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl. 4-cyclobutylpiperazine-I-carboxylate. 2-theta reflection angles are plotted along the X-axis, where the scale scale corresponds to 2.5 2-theta, and where the first mark on the scale corresponds to 5.0 2-theta. The intensities (number of pulses) are plotted along the M axis, where the scale scale corresponds to 1000 pulses, and where the first mark on the scale corresponds to 1000 pulses.

Fi. 2A shows the HCR pattern for Form A of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl citrate salt. 4-cyclobutylpiperazine-I-carboxylate. The 2-theta reflection angles are plotted along the XX 60 axis, where the scale scale corresponds to 1.0 2-theta, and where the first mark on the scale corresponds to 3.0 2-theta. On the Y-axis, the intensities (number of pulses) are plotted, where the mark on the scale corresponds to 1 pulse, and where the first mark on the scale corresponds to 1 pulse.

Fig. 28 shows the proton NMR spectrum for form A of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl citrate salt. 4-cyclobutylpiperazine-1-carboxylate. Chemical shifts (m.h.) are plotted along the X-axis, where the scale scale corresponds to 0.05 m.h., and where the first mark on the scale corresponds to 8.45 m.h. Normalized intensities are plotted along the M axis, where the scale scale corresponds to 0.005, and where the first mark on the scale corresponds to -0.02.

Fi. 2C shows the HCR pattern for form B of 1-(1-methyl-6b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl citrate salt. 4-cyclobutylpiperazine-I-carboxylate. 2-theta reflection angles are plotted along the X-axis, where the scale scale corresponds to 2.5 2-theta, and where the first mark on the scale corresponds to 5.0 2-theta. On the Y axis, the intensities (number of pulses) are plotted, where the scale scale corresponds to 250 pulses, and where the first mark on the scale corresponds to 250 pulses.

Fig. ZA shows the HCR pattern for form A of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl hydrochloride salt. 4-cyclobutylpiperazine-I-carboxylate. 2-theta reflection angles are plotted along the X-axis, where the scale scale corresponds to 1.0 2-theta, and where the first mark on the scale corresponds to 3.0 2-theta. The intensities (number of pulses) are plotted along the M axis, where the scale scale corresponds to 5 pulses, and where the first mark on the scale corresponds to 5 pulses.

Fig. ZB shows the HCR pattern for form B of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl hydrochloride salt. 4-cyclobutylpiperazine-I-carboxylate. 2-theta reflection angles are plotted along the X-axis, where the scale scale corresponds to 2.5 2-theta, and where the first mark on the scale corresponds to 5.0 2-theta. The intensities (number of pulses) are plotted along the M axis, where the scale scale corresponds to 100 pulses, and where the first mark on the scale corresponds to 100 pulses.

Fig. 4A shows the HLC pattern for Form A of 1-(1-methyl-6b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl fumarate salt. 4-cyclobutylpiperazine-I-carboxylate. 2-theta reflection angles are plotted along the X-axis, where the scale scale corresponds to 2.5 2-theta, and where the first mark on the scale corresponds to 5.0 2-theta. The intensities (number of pulses) are plotted along the M axis, where the scale scale corresponds to 1000 pulses, and where the first mark on the scale corresponds to 1000 pulses.

Fig. 48 shows the HCR chart for Form B of 1-(1-methyl-6b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl fumarate salt. 4-cyclobutylpiperazine-I-carboxylate. 2-theta reflection angles are plotted along the X-axis, where the scale scale corresponds to 2.5 2-theta, and where the first mark on the scale corresponds to 5.0 2-theta. On the Y axis, the intensities (number of pulses) are plotted, where the scale scale corresponds to 250 pulses, and where the first mark on the scale corresponds to 250 pulses.

Claims (19)

FORMULA OF THE INVENTION 1. The compound of the formula I (B3)g A o | M (Ro)p XX Ge ak X, r BY ! (I) or its salt, in which B: is isopropyl or cyclobutyl; t takes the value 1; n takes the value 0, 1 or 2; where each РВ2 independently represents halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, C1-halohaloalkyl or C1-4cycloalkyl; or two MR" on the same carbon atom together with the specified carbon atom form C3-cycloalkyl; Chi: represents oxygen; p takes the value 1, and d takes the value 1; BO r takes the value 0, 1 or 2; where each Az is independently a halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, C1-haloalkyloxy or C3-cycloalkyl; or two Bz on the same carbon atom together with the indicated carbon atom form C3.cycloalkyl; A selected from AZ and A4 и5 M (c) и5 M (c) и m De Ve) DA Leads I DAV (Al) where the bond marked with an asterisk is attached to the nitrogen atom; B5 is hydrogen or methyl; 5 takes the value 0, 1 or 2; and each N is independently halogen, C1-4alkyl, C1-4haloalkyl, C1-alkoxy, C1-haloalkyl, or C3-cycloalkyl. 2. A compound selected from the group consisting of 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate; 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate; 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate; 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclopropylpiperazine-1-carboxylate; 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate; 1-(1-ethyl-6-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl 4-isopropylpiperazine-1-carboxylate; 1-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate; 1-(2-oxo-1 2-dihydropyridin-4-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate; 1-(2-oxo-1 2-dihydropyridin-4-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate and 1-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-4- il 4-isopropylpiperazine-1-carboxylate or salts of the specified compounds. 3. The compound of formula I according to claim 1, which is 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate, having the following formula (c) but M--M M M or its salt. 4. The compound of formula I according to claim 1, which is 1-(1-methyl-6b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-isopropylpiperazine-1-carboxylate, having the following formula (c) M tT8- M--M y- M or its salt. 5. The compound of formula I according to claim 1, which is 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl Z0 4-isopropylpiperazine-1-carboxylate, having the following formula (c) M tT83- M -m M Ge) M / or its salt. b. The compound of formula I according to claim 1, which is 1-(1-methyl-6b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate, having the following formula m- km y- -5 / yah in or its salt. 7. The compound of the formula !/ according to claim 1, which is the free form of 1-(1-methyl-6b-oxo-1,6-dihydropyridazin-3-yl)upiperidin-4-yl. 4-cyclobutylpiperazine-1-carboxylate in solid form or 1-(1-methyl-6b-oxo-1,6-dihydropyridazin-3-yl)/piperidin-4-yl salt. 4-cyclobutylpiperazine-1-carboxylate in solid form, where the specified salt is citrate, hydrochloride, fumarate, adipate, maleate or sebacinate of 1-(1-methyl-6b-oxo-1,6-dihydropyridazin-3-yl)piperidin- 4-il. 4-cyclobutylpiperazine-1-carboxylate. 8. The compound according to any of claims 1-7 or its salt for use as a medicinal product. 9. The compound of the formula 1I-1 (Kz)g A o ( M DO (c) and p (p-1) or its salt; where p, ad, r, Az and A take the values indicated for formula I; and Ba represents is an outgoing group. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-7 or a salt thereof and one or more pharmaceutically acceptable carriers. 11. A combination that includes a therapeutically effective amount of a compound according to any one of claims 1-7 or a salt thereof and one or more therapeutic agents active for the treatment of a disorder or disease mediated by NH receptors in a subject. 12. A method of treating a disorder or disease mediated by NZ receptors, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-7 or a salt thereof or a pharmaceutical composition according to claim 10. 13. The method according to claim 12, in which the disorder or disease is selected from the group consisting of obesity, epilepsy, sleep disorders and insomnia with excessive daytime sleepiness, disorders associated with increased fatigue or hypersomnolence, or disorders associated with cognitive functions. 14. The method according to claim 12, in which the disease is narcolepsy. 15. The method according to any one of claims 12-14, in which the compound is administered in combination with one or more other therapeutic agents active to treat in the subject a disorder or disease mediated by NH receptors. Zo 16. Use of a compound according to any one of claims 1-7 or a salt thereof or a pharmaceutical composition according to claim 10 for the manufacture of a medicinal product for the treatment of a disorder or disease mediated by NH receptors. 17. The use of claim 16, wherein the disorder or disease is selected from the group consisting of obesity, epilepsy, sleep disorders and insomnia with excessive daytime sleepiness, disorders associated with increased fatigue or hypersomnolence, or disorders associated with cognitive functions. 18. Use according to claim 16, in which the disease is narcolepsy. 19. Use according to any one of claims 16-18, in which the compound is presented in combination with one or more other therapeutic agents active to treat in a subject a disorder or disease mediated by NZ receptors. clearly : : : what | : : : : ! UN: : : : : NO : N : : : N "o : : : : : No : : : : : N o" i : : : i No N : : : : N SYA : : : N i No N : : : N nk : : : : : No N : : : : N TZ I : : : : NB : N N : : N nah : : : : i NN N : : : : N yah : : : : : NN : : : : : N - : : : : : NICK : : : : : i - i I : N : NNYA N I I N : N as m : : : i No N : : : N "as : : : : : НЯ : : : : : Н - : : : : : НШКН : : : : : Н я ны ши ши ше ши ше - : : : : : НЯ : : : : и т И : : : и : NNYA Н : И : : N snlakt SHHI : : : E : NN : : : : : N -e MO N : : x : BIH : N : : : N a i : : : ije : NIM N : : : : N Z : : : : E : R : : : : : i a : : : : i ! NN She : : : : E how : : : : GYA : NN : N : : : N Zh : : : : EN : NU : : : : : N yin Ya : : : X : NN : Ko : : : N sh : : : : y : SE : SYA : : : N - y : : : n : NO : What : : : N what : : : : NU : hi : n: : : N t I : : : IN V Ri : KN : : : i a : : : : M : NN : I : : : N eeE : ih : : those 1 : r: : : : N ee : і : : STILL : NOT FROM : : : I : Eh : : 1: : NN : HNN : : : : ts : x : : those : No : NN : : : : early x : : TIV : NO : B: : : : i : x : : : y : r : her: : : : N : i : : bo: r. H 11: : : : N i Zh : : HIM NOT H 11: : : N : sh : : Ok: IC ih N NE I : N : TE : : ORE: NENSHU : r: : : : : : E : : RA: ENN IN SCHE : : : I : X : : 1 p: poh N N TG: I : : N : X : |: Oti: poi Ne R: : : N Ku p : 5: N Iraq Nshi N : r : : : : N : i: : ХИ БРНЖР Я: 3: в: Я : : : их : НЯ и гр Н Н 1 GU : : Н Я 1 : В: Ana VE ENN u «y Н х х GENES : : : I 1: : NN sa I xx: Sha sim 21 mi: y : : N i Kk : me ok MU she ? Mch a and h neck: li Ge 0 Ks uakhyutyauinyankichyae ti Kulyk : : : : yny i i o o a V I I GtYA oon ono poronnya pionnn znno i ono porn pon non diarrhea non her 15 ZE 2 ze 5 LP for ia ze Theta (i : V : : : : : : : : : I N N ke IN : : : : : N : y : : : : N v N : : : : : : N I N : : : N -- : : : : : : : : In : : I : ! and N : : : N : N : : : : : : N in what : : : : : : : : : : I : ! in E : : ! : : : | : : | : r» : : I : : : : : B: : I I I F : : I : : B : : B: : I I I GU NU : : : : : : : NU N : : : N EE IN : : : : : : H NU : : : : N N : : : N : : N Z : : : : N i N V : : : : N : VZ : : ! : N h Sh N : : : : : : : NU : : : : N z W : : : : : : : NYA : : : : I and : : : : : and : F : : I : shЖ N : : : : : : N nya : : : : N zh : : : : : r: : | : NA : : I : N and KU : : : : 1: Nk : KN N : : : N «хх т : : : : 1: NYA : Pp : : : : N vk N V : : : EE NU : NYA : : ! : N ; : V : : : KE: NU : NN : : I : N "in : : : : : EE NO : Z : : I : N koh : : : : : : NU : WE : : I : What is it? B i : : : : KE NI : KU : : I : - : N : : : KE NN : pi : : I : N is ve V : : : SE NN : NI : : ! : N I : V : : : KE NN : p : : I : N Eh : V : : : KE NN : Tsi : : I N N sh i : I : I EN : 8 : NU : : Y I -ek - : : : : Ne WE : KI : : : : N I ! ! she and she E : : | E N : : : : More and more N MORE : : : : N : : : : : KO I En I : : : N V : : : NO NO : SHE : : I : N m : : : : NOT YET : YET : : I : ! : : : i : r What Her p : SHE : : I : N N : : : : What is NOT : Ii : : I : ! N : : : KI What NU : KI : : : : N With : In : th : | NN What NKY : EE : : I N N z - : N 1 : Ko EN NBN : 1: I : N I : ova N : : U : IZ EN What UNN K: Z N : : : N N : : і : і Zk Tk YAN : MOH : : : : N і : NI : і і E PeSHRYANIU MI: 8: ti і : і : : Н N : : NO : " Ex 11 PI: ih: NENNY E x : I : N : N : V : V poi 1: RO 4: PENYA x I : и : : Ш : ш p CHE x PI 8: Ri poh 5 MORE oh : N M Y x I schi ikh HNN NYA CHE: pri bin xx r pok 1 t N N Neokan Y : x NN : directed RN I UNN PRIN MNN TSI TIV OLI ZHK yah, : N : TT emodnlzhlya u Ko: odi ly I v sht ay: ХА pl pal U 3 N : ions kn VO p o i a p EN I MO KY CHE NU MU tia i fr r u u rf t fr Z to t d) them Z 5 ztno Z Hek vk i Zh N a z Y i i a E - N ozh Z N Sh i E ma yah N az; re vi nya N nya k Ki - Z N so x not N Eh N sei: x Z N De M as i Z x «j, N rya even Mche g k ka N ia EK o N own N Us. nah KE I N -y N ns E se and yam, and wormwood and p NAME KE Sh, I t and PO y N ya N pjuzhltnia m petllyaayayannia tyu Zh MK and shin E and N blow the Kyivan NI KK kyuzhiniya tyny and POP s HE la h lk is! EM i ŽY tk E tya, N te V ŽILY E pn Y I Shk u s no i nen nzhi me B e i. N x x BO : zhd x I N ee y «KU g More and oo - ey NYA B N Zhe m Ko KE m ve N Mety mryUchtche I EU tt In MUuUtTiT puti VK ur py Teny x Ж 8 x V - ga y x Ж В Ж - Хв хеврсте ижнвустств пыки АХА леж Ж ж и- пух ше U zu B Esh - и How KKU ZE oh и sex M nn Y 1: их Х -111111.1-ии-и----и-и-и1 Zhkchachnchinchin of the CS glass m PPD Ikakkakkakkakkakkakakkakakakakakakakakakakakakakakakakakakakakakaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa y A ot yno zho v KE B Khx x KOH ih- oj uh zhk ih x Х x x KI ДЯ sec x ki kt He Zoo М x ХХ иш их хх Z ож 3 хи TU и КИ 3 5 1 5 Z shcha z y 1 Ku kh ikh y : io Z oj I: SHE ii xx E kh yi potyn Oh Koch (YAKU Zx Х x 3 x Z eat poba z xx Oh ESHEYA pes i a i p p i ia Z xx ALL U SN F i in ZK xx se S y: I: V y Z V Ne v M ХВ NI I IN ti - i p - ke xx sce -E Kk t A « roya sce dk t- s cha he Quixote ХV НеСТІ Fig. 28: Form A of citrate compounds of IA, protonic NAM and ше ше | | | ' koe - | Ko Ki : : : : ' ! | ше ШИ | | ' E ro g ny Е ! : | ! Е ! : РІ ШЭ нщI | ше nn - ВШ РО: И : и : ! : : : Е И : No В: KE I : : : : : I Ж Ne : NE НЯ Ве : : : : : : и кн ше И и ! s NN ЕВ EN : | Е ! : ! ! Because o V SHE SHY | | ! Gn N i. : 1: IN 1:15 KE NE | : : : : : : I m Ki NI shishshshshshi and NYA BR ZHK, NIK xx : r: : : : : : ше и ШЧИ у ши writes every чне шипы ши ши дв и NE KU ME E !!!!! ! 4 | and В у г UPA ne ИЙ : ! : | ! hny nn Zhe uk, nn o shk | shk VL vk rimi EZ IK iE to t Z Z ZATEtv (y Fig. 2C: Citrate form B of compound IA I: there is o she Ku and Ko shk is E y y von N y Z i- Kz i U y t y ZY VE she she: Y ZYM . Ge y U pon - gYa she y dk N i - zh NI - I y g NE e BU y Ka Ne y y V s de N Yaru tTTICHTBEUCHSKuChSKUtTTusvutu tetu Kit kety Kl sen kitrete'ivh Fig. ZA: Form A of compound IA hydrochloride ! : : : | : : ! More | ! ; yes 4 : : : : : I : : : : : E E : : : : : : : ! : : : : M zv ! ! : | : : : KE: | : and t ; : : : NU : : : ГНН : I и ки : : : : НИ : : : ШИ : Н : ш 4 : : : Z : : I Ж : : и ж E : : : m ШЙ I : КИ: : : i i : : : NI : : : NI : : : dO : | ! shk SHE: shi No! | : t E : : : : SHU : : : INV : : Й E E : : i : r I : NYA : : : ee i : : ro: EE : SHE | : and that's it! she she: SHENE! ' and i- NV: vi! : E : goi : : : И: : : и KU ok : KE: VO: : ; y: : : и E YOU : Kk Es: OV a : I TI : : : ж NN TV : Kl BE: 1 NN NENNYA : и NN : : Her seam SHE r NO MORE PIMIN NN Ш Я E NN : : : ЕВ and 7, DAILY NN NNYA AK : и NN : : и E shi shiny shi shi shi shi shi she! I t : Ш:ZNYI DESNY SHNN Ot El : Ш 1: : : и aa -1 : KDKA VNE KN YOUR MINE WITH OUR SHE M SHE SHEU. : : : she Bu pi Esh she SHE SHE ! ! : i : n v chna MNC IN NANCE | NOW Ot. her THES: |; : : i v : : M Me NE NEK EE KNU VE yo : : : : : : VE A N NU I ZM I SHA OKO 13 or : : i E : : B v "i u VK: NNI SHE x 4, : : : Re SHE "B ZU a | : shi she pnshi nn nn chi yy i y : : : Н : Н : : : их "акры: щ U ще t | | | v a nn nn o p i a a M a g KU ih 25 t 33 Z A- Theta Fig. 3B: Form B of the hydrochloride of the compound IA nn, mm vv io pip pava iii introduced under vapors half introduced divisions fella z : : , : : : I "7 : : : B : B I is : : H : : : H them With : : : : : I ze ! : : i : V N - 1 : N 7 : : N I : NU : : : N Kz : : MORE | : : i 1 I NU i : : N sho eyue-: : NI V : : i - : : i : | : ' dk I : iE 1: : : N siy : : NO : : : I also : : and : : E! and 4 : n I ! : : de I : и KE: : V i eh : : NN p: : : N Zh : : Ne BE : : I Z I : Iii Z: : E I sh : : Iii KK GE : : i : : her MORE SHE : : ! her: her and. AS. | E: I: Ii ZHE KO; : I I : NIA PO: x Z 5 : N I : Not MV ENN i : i I I KE GNE i INN : : N : : Z SCHE NOT OO N : i m: : : NN NV x EN 3 : N : : I NN NN x SHHI Z . : Н : : х НН НН МОЖ и х : i : : E i NOT ЕВ Z В! : and : Ko: No and NE BOB KE NO : I Z x N pi them NECHNI PO EE y : N i o: YAR in SCHE ri SCHE and them : kove de Biy em NI SHE NI U U YE I " and 1 Mol ndlku mi u i SU De en MK NE 5 UK k N : naim m NN A KK p p M o V i PE VE OD U S Dy - 15 5 U 2 KO cha Z-Keta 2 fig. 4A Form A of compound IA fumarate sly nn zhvs'snvzhnT'vtchvsttzhvyivyvtntNnNnnchvsTvTvyTzhnTzhzhchTzhntTtTtTzhntTtTnTtTtTntTnntntnTtTtTchnchtchtttntTtnntnnntttnnnntTtTtTtTtnttntntntpntpnpntpnnn : I : I : I : I : I : I : : I : : and I : : : : : : N : : N : N same" N : : : : : : KK: : : N : N v i : : : : Or R : : : : E E : : : : : : : Co. : : : : and OVC Z : : ! : : | ! 1 : : ! ! ! Kk N : : : : : : (I : : N : N Z i : : : : other things : : : : and t i : : : : : o: Her: : : : : N E i : : : NI : r ENN : : : : and how and : : : nya and EN X: : : : : and it le NI | shi shi shi j I : : : go ii BOR : : : : I J : : : : NO: U BOR: : : : : and I : : : them EM RE : : : : I also : : : OV KK OV I : : : : and the same and : : : NI YA EOROV V: : : : : and Z Z : : : shi MNE SCHE ZY : : : : i ! i | shin shi nshish ! : ! E : Zaee n ro : nin NN YN BIO EI R OZ : I : : I N : I : : EE: NYA i OO DE : их, : : : : Н N : 3 : : V: NYA pr: o: ШЭ что и 5: : Н : : N i SHE ME : NNYA Y i A OO SHCHEBII OYI E : : : : i y NI IN MY NIGHT IE NOT BEK 5. : : : I x N i : i : GU IN Koh NEO: KONKU shocks 1 : N : N 8 ni MEE Nh, EB: YOU OYA : I : i I : EVERYDAY SHE MAE NN Ne BIV IB y: y : I and I I A BIV PE EN CHEN AMINY OUR NE SHE A u and i : ni Z NE M KO V POD I V V Z DK U I PDM KAVI I KEN SHCHI yah y and she ши пи по а о п пие 5 1 iz tt z zo m y Cat Fig. 4Ш: Form B fumarate of compound IA