The invention relates to new 4-substituted piperidine derivative that is related to ones antagonists neirokinina 2 (NK), which can be used, for example, in the treatment of diseases such as asthma, and the way they are received. 4-Substituted derivatives of piperidine derivatives correspond to the General formula I, where the values of m, D, G, J, L, M have the meanings indicated in the claims. Method of producing compounds of the formula I is the compound of formula I is subjected to condensation with Deaktivierung carbonyl or thiocarbonyl derivative, respectively, followed if necessary by oxidation obtained piperidino derived to obtain the N-oxide, or by alkylation of compounds, where R12
- alkyl. 2 C. and 7 C.p. f-crystals, 3 ill., 1 PL.
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The present invention relates to therapeutic compounds, and more specifically, to novel 4-substituted derivatives of piperidine, which are antagonists pharmacological action of one of the endogenous neuropeptide tachykinins known as neurokinin, especially on the receptor neirokinina 2 (NC). New therapeutic heterocycles can be which may have implications for the treatment of those diseases, in which plays a significant role NK-receptor, for example in the treatment of asthma and other closely related conditions. The invention also provides pharmaceutical compositions containing the new therapeutic compounds for use in the treatment of such diseases, methods of their use, and how and intermediate compounds for the production of new therapeutic heterocycles.
Neurokinin mammals are a class of peptide neurotransmitters found in the peripheral and Central nervous systems. Three main neurokinins are Substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB). There are also extended through the terminal nitrogen atom of the form, at least in the case of NKA. Also known at least three types of receptors for the three main neurokinins. Based on the relative selectivity to neurokinin the agonists SP, NKA and NKB, receptors are classified as receptor neirokinina 1 (NK1) receptor neirokinina 2 (NK2) and receptor neirokinina 3 (NK3), respectively. On the periphery of neurokinin SP and NKA are localized in the C-afferent sensory nerve cells, which are characterized by non-mielinizirovannykh nerve endings, known as C-fibers, and are distinguished by villages in the epithelium of the respiratory tract, and thecinema known to cause profound effects that undoubtedly similar to many of the symptoms observed in asthma. Symptoms arising in the selection or the introduction of thekennel in the respiratory tract of mammals include bronchostenosis, increased microvascular permeability, vasodilatation and activation of mast cells. Thus, thecinema involved in the pathophysiological process and hypersensitivity of the respiratory tract, which are observed in asthmatic phenomena; and the blockade highlight thekennel may be useful in the treatment of asthma and related conditions.
It was reported peptide antagonists of NK2. For example, as selective NK2 antagonist described cyclic Hexapeptide known as L-659,877. Known ones and NK2 antagonists, for example, some peptides presented in the European patent applications N 428434, 474561, 512901, 512902, 515240 and 559538. A number of peptide antagonists of NK2 described in International application WO 94/10146.
We have opened a number of new ones NK2 antagonists, which constitute the basis of the present invention. One of the objects of the present invention are 4-substituted derivatives of piperidine, in which the substituent in position 4 of the present is-is derived, presented below in Example 1, which is a potential NK2 antagonist when checking in vitro, which is described below in experiment A, and the functional assessment, described below in experiment B.
In accordance with the present invention offers the claimed Compound which is a compound of formula I (formula below after Examples, together with other formulae referred to by Roman numerals), where:
m takes on the values 2,
D represents a residue of formula Ia, where
Q represents phenyl which may contain one or two substituent selected independently of one another from the group comprising halogen atom,
represents a hydrogen atom,
represents a hydrogen atom or methyl;
represents phenyl, unsubstituted or substituted by one or more atoms of halogen,
hydroxy, (1-4C)alkoxy or (1-4C)alkyl;
G denotes a simple link;
J means oxo or thioxo group;
M stands for-O-, -S - or-NR12
L means L1
represents a hydrogen atom, a C1-3
=NC (= 0) CH2
represents methylene, trimethylene or tetramethylene;
or N-oxide compounds of formula I at the nitrogen atom piperidino fragment, denoted as ;
or pharmaceutically acceptable salts of these compounds of formula I.
The Quaternary ammonium salt of the compounds of the formula I, in which the nitrogen atom piperidino fragment, denoted as , is a tetravalent ammonium nitrogen atom, where the fourth radical at this atom represents (1-4C)alkyl or benzyl and the associated counterion is a pharmaceutically acceptable anion.
It should be noted that the compound of the formula I contain one or more asymmetrically substituted carbon atoms so that these compounds can be isolated in the form of optically active isomers, racemic and/or diastereoisomeric forms. It should also be noted that the compound of formula I may exist in tautomeric forms, and that this connection may be preformism. It should be understood that the present invention encompasses any racemic, optically active, diastereoisomers, tautomeric, polymorphic or stereoisomeric form, or mixtures thereof, and this form has the properties of antisdale of the racemate or by synthesis from optically active starting materials) and how to determine the properties of the NK2 antagonist using standard experiments, described next. Preferred may be the use of the compounds of formula I in the form that contains, for example, at least 95, 98, or 99% enantiomer excess. In addition, the preferred may be the use of the compounds of formula I, which corresponds to the compound of formula Ic, in the form of containing, such as 95, 98, or 99% enantiomeric excess of the form C (S)-configuration at the centre, which is represented in the formula by an asterisk*
In the present description, the substituents Ra
and other means the total radicals and have no other values. It should be understood that the General term "(1-3C)alkyl" includes both linear and branched alkyl radicals, and references to individual alkyl radical such as "propyl" only a linear radical ("normal"), and isomeric branched chain, such as "isopropyl" are called separately. Similar techniques are used for other General groups, for example alkoxy groups, alkanoyl groups and other halogen Atoms are fluorine, chlorine, bromine or iodine.
Below for illustration only, but not to exclude other values within the specified ranges, lists the individual values for radicalgenerating values (1-6C) alkyl substituent is methyl, ethyl, propyl, isopropyl and butyl.
Particular values of (1-3C) alkyl substituent is methyl or ethyl.
When D represents the formula Ia, Qa
represents a hydrogen atom, a specific value of the substituent R1
is methyl, and the specific value of the substituent R2
. The specific value of the substituent R3
is phenyl, and, more specifically, phenyl, where the aryl (or phenyl) may contain as a substituent one or two atoms of chlorine or fluorine.
The specific value of Q is, for example, phenyl, which may contain one or two substituent selected from the group comprising halogen atom, triptorelin group or methylenedioxy group; more specifically, Q is a 3,4-dichlorophenyl or 3,4-methylidenedioxolan.
The specific value of Q is, for example, a single bond or a methylene group; or a single bond. The specific value of J is, for example, oxo, thioxo, imino, methylimino or ethylimino; and, more specifically, oxo or thioxo. The specific value of M represents a hydroxy, thio or NH; and, more specifically, hydroxy or NR. The specific value of L is, for example, ethylene, CIS-vinile or t the order of the compounds of formula Ic, where: Qb
represents phenyl which contains one or two substituent, independently from each other selected from the group comprising halogen atom, and G, J, L and M are taking any of the values defined for the corresponding radical in a compound of formula I; or a N-oxide specified with the compounds of formula I at the nitrogen atom of the piperidine, denoted by ; or a pharmaceutically acceptable salt of the compounds of formula I and the N-oxide; or a Quaternary ammonium salt of the compounds of the formula I, in which the nitrogen atom in piperidinium fragment, denoted by , represents a tetravalent ammonium nitrogen atom, where the fourth radical on the nitrogen atom is (1-4C)alkyl or benzyl and the associated counterion is a pharmaceutically acceptable anion.
Another specific group of compounds of formula I are the compounds of formula Ic, where: R12
represents a hydrogen atom or (1-3C)alkyl; T and U represents a hydrogen atom; andw
is methyl; and their pharmaceutically acceptable salts.
The preferred compounds are (S)-N-[2-(3,4-dichlorophenyl) -4-[4-(2-oxopyrrolidin-1-yl)piperidino] butyl]-N-methylbenzamide; (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(3-methyl-2-oxopyrimidine] butyl] -N-methylbenzamide; and (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxopyrrolidin-1-yl)piperidino] butyl]-N-ethylbenzamide; and their pharmaceutically acceptable salts.
Specific compounds described in the respective Examples.
Pharmaceutically acceptable salt is a salt obtained by use of acid, which gives a physiologically acceptable anion. Pharmaceutically acceptable salts are salts that are formed on the basis of a strong inorganic or organic acids, supplying physiologically acceptable anion, such as, for example, hydrochloric, sulfuric, phosphoric, methansulfonate acid or n - toluensulfonate.
Consider the connection can be obtained by methods which include well-known in the chemistry of the ways to obtain structurally similar heterocyclic compounds.
Such methods and intermediate compounds for obtaining the compounds of formula I or N-oxides of the compounds of formula I in piperidinium the nitrogen atom, denote , or pharmaceutically acceptable salts of the compounds of the formula I or their N-oxides; or Quaternary ammonium salts of the above compounds of formula I, in which piperidinyl the nitrogen atom, denote the I (1-4C)-alkyl or benzyl, and the counterion is a pharmaceutically acceptable anion; which are defined above, are another characteristic of the present invention, and illustrates the following techniques, in which, unless otherwise stated, values are common radicals take the values defined above.
(a) Alkylation of the piperidine of formula II with an aldehyde of the formula IV, reductive alkylation or by using an alkylating agent of formula V, where the Deputy is a leaving group. Typical leaving groups are iodine, bromine, methanesulfonate, p-toluensulfonate, triftorbyenzola and other Alkylation is preferably carried out by conventional reductive alkylation, for example, in accordance with the procedure described in Example 1, by acid catalyzed education in city ammonium salts, followed by recovery of lamborghini.com sodium in an alcohol solvent.
(b) For compounds of formula I, where G is a single bond; J is an oxo or thioxo, respectively; M represents a hydroxy, thio or NP12
L takes on the values L1
; cyclization of compounds of formula III using Deaktivierung derived carboxylic M carboxylic acids include, for example, 1,1'-carbonyldiimidazole, chloroformiate (such as methylchloroform, ethylchloride or phenylcarbamate) and bicarbonate, as well as phosgene, diphosgene and triphosgene; to Deaktivierung thiocarbonyl derivatives include, for example, 1,1'-thiocarbonyldi-2(1H)-pyridone, 1,1'-thiocarbonyldiimidazole, phenylbarbituric and thiophosgene. The cyclization is usually carried out in an inert solvent, such as chloroform, tetrahydrofuran or toluene, at a temperature from about room temperature to the boiling temperature of the reaction mixture, for example, in accordance with the procedure described in Example 3. If deaktivirovannovo carboxylic acid derivative or deaktivirovannovo thiocarbonyl derivative is the acid chloride of the acid, it may be preferable to conduct the cyclization in the presence of a base as acid acceptor, such as, for example, triethylamine.
(C) For compounds of formula I, which has the formula Ic, the interaction of the amine of formula VIII c with a suitable acid chloride acid. The reaction can be carried out in an inert solvent such as tetrahydrofuran, diethyl ether, toluene, chloroform or methylene chloride, at a temperature in the range from -78 to 100(g) For compounds of formula I, which has the formula Ic, the interaction of the amine of formula VII with an activated derivative of carboxylic acid. The reaction can be carried out in an inert solvent such as tetrahydrofuran, diethyl ether, toluene, chloroform or methylene chloride, at a temperature in the range from -78 to 100oC, preferably in the range from -20 to 50oC, in the presence of a suitable activating agent, for example, in the presence of hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The reaction can be conducted, for example, in conditions similar to the conditions described in Example 20.(d) For the N-oxide compounds of formula I in piperidino nitrogen atom, denoted oxidation piperidino the nitrogen atom, denote , using conventional techniques, for example, by oxidation with hydrogen peroxide in methanol, peracetic acid or 3-chloroperoxybenzoic acid in an inert solvent (such as dichloromethane) or dioxirane in acetone. Suitable for carrying out the reaction conditions described in Example 21.(e) For compounds of formula I, where the substituent R12- represents (1-3C)alkyl, RaOC(=O)CH2or RbRCNC(=O)CH2-, Alcoa by using the appropriate alkylating agent. The alkylation can be carried out in an inert solvent, such as tetrahydrofuran, diethyl ether, toluene or 1,2-dimethoxyethane, at a temperature in the range from -78 to 100oC, preferably in the range from 0 to 50oC, in the presence of a suitable base. The relevant conditions described in Example 22.(g) Quaternary ammonium salts of the compounds of formula I, alkylation piperidino the nitrogen atom indicated in the compound of formula I , using the appropriate alkylating agent. The alkylation can be carried out in an inert solvent such as tetrahydrofuran, diethyl ether, toluene or 1,2-dimethoxyethane, at a temperature in the range from -78 to 100oC, preferably in the range from 0 to 50oC, in the presence of a suitable base.In some cases, when carrying out the above methods preferably use of protective groups, or at all stages of the reaction, or at some stage. The protective group can then be removed.In any of the methods described above, when required to obtain pharmaceutically acceptable salts of the compounds of formula I or pharmaceutically acceptable salt of R-oxide, seeding N-oxide acid, which supplies a physiologically acceptable counterion or by any other known methods.It should be noted that some of the optional substituents of the considered Compounds can be introduced using standard reactions of aromatic substitution or obtained by conventional modifications of functional groups before or after the above-described methods and, thus, also included in the invention the object "method". Such reactions and modifications of functional groups include, for example, the introduction of a nitro group, or halogen atom, and the restoration of the nitro-groups. Reagents and conditions for such reactions are well known in chemistry.If the raw materials necessary for carrying out the methods described above, are not commercial products, they can be obtained by methods which are selected from among the standard chemistry of heterocyclic compounds, methods that are similar to the techniques of synthesis of known, structurally similar compounds, as well as from a number of techniques similar to those described above, or the techniques described in the Examples. Original products and methods for their production are also additional object of the present invention.