JP2008239618A - Pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition with a thiomorpholine compound having high tachykinin receptor antagonistic activity as an active ingredient. <P>SOLUTION: The pharmaceutical composition contains, as the active ingredient, a thiomorpholine compound of general formula [1] or a pharmacologically acceptable salt thereof. This pharmaceutical composition is effective as a prophylactic or curative agent for diseases selected from inflammation, allergic diseases, pain, migraine, neuralgia, pruritus, cough, central nervous system disorders, digestive system diseases, nausea, vomiting, miction abnormality, circulatory system diseases and immunopathy. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition comprising a novel thiomorpholine compound having excellent tachykinin receptor antagonistic activity as an active ingredient.

  Tachykinin is a general term for a group of neuropeptides. Substance P (hereinafter referred to as SP), neurokinin A, and neurokinin B are known in mammals, and these peptides are the receptors ( It is known to exhibit various biological activities by binding to neurokinin 1, neurokinin 2, and neurokinin 3). Among them, SP is one of the longest and most extensively studied neuropeptides among which 11 amino acids were found in horse intestinal intestinal extracts in 1931 and the structure was determined in 1971. Is a peptide consisting of

  SP is widely distributed in the central and peripheral nervous systems, and functions as a transmitter of primary sensory neurons, as well as vasodilatory action, vascular permeability enhancing action, smooth muscle contraction action, nerve cell excitatory action, salivary secretion action. Physiological activities such as diuretic enhancement and immunity. In particular, it is known that SP released from the terminal of the dorsal horn of the spinal cord by pain impulses conveys pain information to secondary neurons, and SP released from the peripheral terminal induces an inflammatory reaction at its receptor. Therefore, it is considered that SP is involved in various pathological conditions (for example, pain, inflammation, allergy, frequent urination, urinary incontinence, respiratory tract disease, psychosis, depression, anxiety, vomiting, etc.) SP is also considered to be involved in Alzheimer-type dementia [Review: Physiological Reviews, 73, 229-308 (1993) (Non-Patent Document 1), Journal Of Autonomic Pharmacology, Vol. 13, pp. 23-93 (1993) (Non-patent Document 2)].

  Currently, as a compound having tachykinin receptor antagonistic activity, Patent Document 1 discloses:

(Wherein R ¹ is hydrogen or fluoro)
And a pharmacologically acceptable acid addition salt thereof.

  In addition, in Patent Document 2,

[Wherein, R represents a halogen atom or a C _1-4 alkyl group;
R ₁ represents a C _1-4 alkyl group;
R ₂ represents hydrogen or a C _1-4 alkyl group;
R ₃ represents hydrogen or a C _1-4 alkyl group;
R ₄ represents a trifluoromethyl group;
R ₅ represents hydrogen, a C _1-4 alkyl group or C (O) R ₆ ;
R ₆ represents C _1-4 alkyl, C _3-7 cycloalkyl, NH (C _1-4 alkyl) or N (C _1-4 alkyl) ₂ ;
m is 0 or an integer from 1 to 3;
n is an integer of 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, Patent Document 3,

[Where:
R is halogen or C _1-4 alkyl;
R ₁ is hydrogen or C _1-4 alkyl;
R ₂ is hydrogen, C _1-4 alkyl, or R ₂ together with R ₃ represents C _3-7 cycloalkyl;
R ₃ is hydrogen, C _1-4 alkyl, C _3-7 cycloalkyl or C _3-6 alkenyl; or R ₁ and R ₃ together with the nitrogen and carbon atoms to which they are attached respectively, Represents a 6-membered heterocyclic group;
R ₄ is trifluoromethyl, C _1-4 alkyl, C _1-4 alkoxy, trifluoromethoxy or halogen;
R ₅ is hydrogen and R ₆ is NR ₇ R ₈ or R ₅ is NR ₈ R ₉ and R ₆ is hydrogen;
R ₇ is hydrogen or C _1-4 alkyl, or R ₇ and R ₈ together with the nitrogen to which they are attached represent an oxygen-containing saturated 5- to 7-membered heterocyclic group;
R ₈ is saturated 5 to 7 containing 1 to 3 heteroatoms selected from hydrogen, phenyl, C _3-7 cycloalkyl, (CH ₂ ) pC (O) NR ₁₀ R ₁₁ , oxygen, sulfur and nitrogen. Hajime Tamaki members _{(C 1-4} alkyl _may be substituted with _{S (O) 2 C 1-4} alkyl or C _{(O) C 1-4} alkyl), selected from oxygen, sulfur and nitrogen 5-membered heteroaryl group containing 1 to 3 heteroatoms (optionally substituted with C _1-4 alkyl S (O) ₂ C _1-4 alkyl or C (O) C _1-4 alkyl) Or R ₈ is a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms (C _1-4 alkyl, S (O) ₂ C _1-4 alkyl or C (O) C _1-4 alkyl Or may be substituted with Fluorine _{R 8} is phenyl _{(C 1-4} alkyl, optionally substituted with _{C (O)} C _1-4 alkyl or halogen), = _{O, C 3-7} cycloalkyl, hydroxy, amino, dimethylamino A C _1-6 alkyl group optionally substituted with 1 or 2 groups selected from aminocarbonyl, C _1-4 alkoxy or trifluoromethyl;
R ₉ is hydrogen, C _1-4 alkyl, or R ₉ and R ₈ together with the nitrogen to which they are attached contain another heteroatom selected from oxygen, sulfur and nitrogen. _{1 selected} from C _1-4 alkyl, ═O, S (O) ₂ C _1-4 alkyl, C (O) C _3-7 cycloalkyl or C (O) C _1-4 alkyl. Or a 5- to 7-membered heterocyclic group optionally substituted by 2 groups;
R ₁₀ and R ₁₁ are independently hydrogen or a C _1-4 alkyl group;
X is a nitrogen atom and Y is CH or X is CH and Y is nitrogen;
m is 0 or an integer from 1 to 3;
n is an integer from 1 to 3;
p is 0, 1 or 2]
Or a pharmaceutically acceptable salt and solvate thereof.

  Furthermore, Patent Document 4 includes:

(In the formula, ring A represents an optionally substituted benzene ring, ring B represents an optionally substituted benzene ring, and R ¹ represents an optionally substituted alkyl. Group, a hydroxyl group which may have a substituent, a thiol group having a substituent, a carbonyl group having a substituent, a sulfinyl group having a substituent, and a substituent Sulfonyl group or formula:

A group represented by
R ¹¹ and R ¹² are the same or different and are each a hydrogen atom, a carbonyl group having a substituent, a sulfonyl group having a substituent, an optionally substituted alkyl group or a nitrogen atom as a hetero atom A heterocyclic group containing 1 to 4 atoms selected from an atom, an oxygen atom and a sulfur atom, the heterocyclic group optionally having a substituent, and further included in the heterocyclic group The nitrogen atoms may be oxidized or together with adjacent nitrogen atoms bonded to each other together with a piperidino group, azacycloheptyl group, pyrrolidino group, imidazolidinyl group, hexahydropyrimidinyl group, thiazolidyl group, morpholino group, It represents that a heterocyclic group selected from a triazolyl group, a tetrazolyl group and a prynyl group is formed, and the heterocyclic group is a substituent. May have, may be further nitrogen atom contained in the heterocyclic group is oxidized, R ² is a hydrogen atom, hydroxyl group which may have a substituent, have a substituent Represents an amino group which may have a substituent, an alkyl group which may have a substituent, a carbonyl group having a substituent or a halogen atom, and Z represents an oxygen atom or a group represented by —N (R ³ ) —. , R ³ represents a hydrogen atom or an optionally substituted alkyl group, and R ⁴ represents a hydrogen atom or an optionally substituted alkyl group. )
Or a pharmacologically acceptable salt thereof.
Physiological Reviews, 73, 229-308 (1993). Journal of Autonomic Pharmacology, 13: 23-93 (1993). International Publication No. 2003/011860 Pamphlet International Publication No. 2002/032867 Pamphlet International Publication No. 2003/066589 Pamphlet International Publication No. 2003/099787 Pamphlet

  Currently, it has excellent tachykinin receptor antagonism (especially SP receptor antagonism) as a therapeutic agent for the various pathological conditions (especially vomiting, depression or dysuria), and is safe and durable (metabolism, in vivo A compound that is sufficiently satisfactory in terms of kinetics and absorbability) has not yet been found. Therefore, it is desired to develop a pharmaceutical composition comprising as an active ingredient a compound that has an excellent tachykinin receptor antagonism and can sufficiently satisfy clinical effects as a therapeutic agent for the disease state.

  The present invention relates to general formula [I]

(In the formula, ring A represents a benzene ring which may have a substituent.
Ring B represents a benzene ring which may have a substituent.
R ¹ represents a hydrogen atom, a hydroxyl group which may have a substituent, an amino group which may have a substituent, an alkyl group which may have a substituent, or a carbonyl group which has a substituent. Or represents a halogen atom.
R ² represents a hydrogen atom or an alkyl group which may have a substituent.
R ^3a and R ^3b are the same or different and each represents a hydrogen atom or an alkyl group which may have a substituent, or a group which is bonded at a terminal to form an alkylene group.
n represents an integer of 1 or 2. )
And a pharmacologically acceptable salt thereof as an active ingredient.

  The present invention relates to a pharmaceutical composition comprising as an active ingredient a compound having excellent tachykinin receptor antagonistic activity and clinically satisfactory from the viewpoint of safety and sustainability (metabolism, pharmacokinetics, absorbability), etc. It is to provide.

  In the present invention, ring A of compound [I], which is an active ingredient, represents a benzene ring which may have a substituent. Examples of the substituent on the benzene ring include an alkyl group, a halogen atom, a cyano group, and a protected group. Examples thereof may include a hydroxyl group or an alkoxy group. Ring A may have 1 to 3 of these substituents which may be the same or different.

  In the present invention, ring B of compound [I], which is an active ingredient, represents a benzene ring which may have a substituent. Examples of the substituent on the benzene ring include a trihalogenoalkyl group, a halogen atom, a cyano group, phenyl Examples thereof include a heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a hetero atom, an alkyl group, an optionally protected hydroxyl group or an alkoxy group. Ring B may have 1 to 3 of the same or different substituents.

  Preferred examples of ring A and ring B in compound [I] which is an active ingredient of the present invention include, for example, ring A represented by the formula:

And ring B is represented by the formula:

And A ¹ , A ² and A ³ are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, an optionally protected hydroxyl group or an alkoxy group, and B ¹ , B ² And B ³ are the same or different and each represents a hydrogen atom, a trihalogenoalkyl group, a halogen atom, a cyano group, a phenyl group, a hetero atom containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a hetero atom. The compound which is a cyclic group, an alkyl group, a hydroxyl group which may be protected, or an alkoxy group is mentioned. Examples of the trihalogenoalkyl group include a trifluoromethyl group and trichloromethyl. Examples of the heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as a hetero atom include a tetrazolyl group.

  In the compound which is the active ingredient of the present invention or the compound used in the present invention, the protective group for the hydroxyl group which may be protected includes an arylalkyl group which may have a substituent and a substituent. Examples thereof include conventional protective groups such as silyl group and acyl group. Among these, preferred are, for example, arylalkyl groups such as benzyl group and phenethyl group, silyl groups having a substituent such as tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, formyl group, and acetyl group. And acyl groups such as propionyl group, malonyl group, acryloyl group and benzoyl group.

In the compound [I] which is an active ingredient of the present invention, R ¹ has a hydrogen atom, a hydroxyl group which may have a substituent, an amino group which may have a substituent, or a substituent. And an optionally substituted alkyl group, a carbonyl group having a substituent, or a halogen atom.

In the compound [I] which is an active ingredient of the present invention, the substituent of the hydroxyl group which may have the substituent of R ¹ includes an alkyl group.

In the compound [I] which is an active ingredient of the present invention, examples of the substituent of the amino group which may have the substituent of R ¹ include an alkyl group.

In the compound [I] which is an active ingredient of the present invention, examples of the substituent of the alkyl group which may have the substituent of R ¹ include an alkoxy group.

In the compound [I] which is an active ingredient of the present invention, examples of the substituent of the carbonyl group having a substituent of R ¹ include a hydroxyl group, an alkoxy group, and an alkylamino group.

In compound [I] which is an active ingredient of the present invention, examples of R ² include a hydrogen atom or an alkyl group which may have a substituent. Examples of the substituent of the alkyl group that may have a substituent for R ² include a hydroxyl group, an alkanoyl group, a halogen atom, an alkoxy group, and an alkylamino group.

In the compound [I] which is an active ingredient of the present invention, R ^3a and R ^3b are the same or different and each represents a hydrogen atom or an alkyl group which may have a substituent, or bonded at the end. Examples thereof include a group that forms an alkylene group. Examples of the substituent of the alkyl group that may have a substituent include a hydroxyl group.

  In compound [I] which is an active ingredient of the present invention, n may be an integer of 1 or 2.

  As compound [I] which is an active ingredient of the present invention, ring A is represented by the formula:

Wherein A ¹ represents an alkyl group, A ² represents a halogen atom, and ring B is represented by the formula:

Wherein B ¹ represents a trihalogenoalkyl group, B ² represents a trihalogenoalkyl group, R ¹ represents a hydrogen atom, R ² represents an alkyl group, and R ^3a and R ^3b represent The compounds which are the same or different and are a hydrogen atom or an alkyl group are preferred. The compound [I], which is an active ingredient of the present invention, is preferably a compound where n is 2.

Moreover, in the compound which is an active ingredient of this invention, as a preferable compound, it is the compound chosen from the following (a)-(g), or its pharmacologically acceptable salt.
(A) 1,1-dioxo-4- (S)-[1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R )-(4-Fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,
(B) 1,1-dioxo-4- (R)-[1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R )-(4-Fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,
(C) 1,1-dioxo-4- (S)-[1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R )-(4-Fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,
(D) 1,1-dioxo-4- (R)-[1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R )-(4-Fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,
(E) 1,1-dioxo-4- (S)-[1- {N- (3,5-bistrifluoromethylphenyl) methyl-N-methyl} -2- (R)-(4-fluoro-2 -Methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,
(F) 1,1-dioxo-4- (R)-[1- {N- (3,5-bistrifluoromethylphenyl) methyl-N-methyl} -2- (R)-(4-fluoro-2 -Methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine and (g) 4- (S)-[1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl}- N-methyl] -2- (R)-(4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] -1-oxothiomorpholine.

  Compound [I], which is an active ingredient of the present invention, can be used for pharmaceutical use in a free form or in the form of a pharmacologically acceptable salt.

  Examples of the pharmacologically acceptable salt of the compound [I] which is an active ingredient of the present invention include inorganic acid salts such as hydrochloride, sulfate, phosphate and hydrobromide, acetate, and fumaric acid. And organic acid salts such as salts, oxalates, citrates, methanesulfonates, benzenesulfonates, tosylates, maleates, succinates and tartrates.

  In addition, the compound [I] which is an active ingredient of the present invention or a pharmacologically acceptable salt thereof includes any of its internal salts, solvates or hydrates thereof.

  The compound [I], which is an active ingredient of the present invention, can exist as an optical isomer based on an asymmetric atom, but the present invention includes any of these optical isomers and mixtures thereof. In the present invention, among these optical isomers, a compound in which the 2-position of the piperidine ring (the connection position of ring A) is R is preferable.

  The compound [I] which is an active ingredient of the present invention or a pharmacologically acceptable salt thereof has an excellent tachykinin receptor antagonistic action, particularly an SP receptor antagonistic action, and is suitable for mammals (eg, mice, guinea pigs, gerbils). , Ferrets, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.) or inflammation or allergic diseases (eg, atopy, dermatitis, herpes, psoriasis, asthma, bronchitis, sputum, rhinitis, Rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, conjunctivitis, ophthalmitis, cystitis, etc.), pain, migraine, neuralgia, pruritus, cough, and central nervous system diseases (eg, schizophrenia, Parkinson's disease) , Depression, anxiety, psychosomatic disease, morphine dependence, dementia (eg, Alzheimer's disease, etc.), digestive disorders (eg, irritable bowel disease, ulcer Abnormalities caused by ulcerative colitis, Crohn's disease, urease-positive spiral gram-negative bacteria (eg, Helicobacter pylori) (eg, gastritis, gastric ulcer, etc.), nausea, vomiting, dysuria (eg, frequent urination, Urinary incontinence, etc.), cardiovascular diseases (for example, angina pectoris, hypertension, heart failure, thrombosis, etc.) and safe abnormalities such as immune abnormalities are useful. In particular, the compound [I] which is an active ingredient of the present invention or a pharmacologically acceptable salt thereof has a high ability to enter the brain and is less likely to lead to toxicity (high safety), and has side effects. Since it is hardly shown, it is useful as a preventive or therapeutic agent for central nervous system diseases such as vomiting and depression, and micturition abnormalities such as frequent urination.

  The compound which is an active ingredient of the present invention or a pharmacologically acceptable salt thereof can be obtained by, for example, the method described in European Journal of Pharmacology Vol.254, pp. 221-227 (1994). Similarly, the neurokinin-1 receptor binding action can be measured, according to the method described in European Journal of Pharmacology 265, 179-183 (1994), The effect on neurokinin-1 receptor agonist-induced behavior can be measured, and Journal of Urology, Vol. 155, No. 1, pages 355-360 (1996) In accordance with the method, it is possible to measure the urinary frequency suppression effect.

  Compound [I] and its pharmacologically acceptable salt, which are the active ingredients of the present invention, can be administered orally or parenterally, using a pharmaceutical carrier usually used for oral or parenteral administration. Thus, a suitable preparation can be obtained. Examples of such pharmaceutical carriers include binders (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, corn starch, potassium phosphate, sorbit, glycine, etc.), lubricants ( Examples thereof include magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrating agents (potato starch, etc.) and wetting agents (anhydrous sodium lauryl sulfate, etc.). In addition, in the case of oral administration, these pharmaceutical preparations may be solid preparations such as tablets, granules, capsules and powders, or liquid preparations such as solutions, suspensions and emulsions. On the other hand, in the case of parenteral administration, for example, injection water, physiological saline, glucose aqueous solution or the like can be used as an injection, a drip infusion, or a suppository.

  The dose of compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof varies depending on the administration method, patient age, body weight, condition, or degree of disease, but is usually administered per day. The amount is 0.01-20 mg / kg, especially 0.01-10 mg / kg for oral administration, 0.01-10 mg / kg, especially 0.01-1 mg / kg for parenteral administration. kg is preferred.

[Method A]
The compound [I], which is an active ingredient of the present invention, is represented by, for example, the general formula [II]

(In the formula, ring A represents a benzene ring which may have a substituent.
Ring B represents a benzene ring which may have a substituent.
R ¹ represents a hydrogen atom, a hydroxyl group which may have a substituent, an amino group which may have a substituent, an alkyl group which may have a substituent, or a carbonyl group which has a substituent. Or represents a halogen atom.
R ² represents a hydrogen atom or an alkyl group which may have a substituent.
R ^3a and R ^3b are the same or different and each represents a hydrogen atom or an alkyl group which may have a substituent, or a group which is bonded at a terminal to form an alkylene group. )
Can be produced by reacting in the presence of an oxidizing agent.

[Method B]
The compound [I], which is an active ingredient of the present invention, is represented by, for example, the general formula [III]

(In the formula, ring A and R ¹ have the same meaning as described above.)
And a compound of the general formula [IV]

(In the formula, ring B, R ² , R ^3a and R ^3b have the same meaning as described above.)
It can be manufactured by reacting with the compound shown by presence of a urea agent.

[Method C]
The compound [I], which is an active ingredient of the present invention, is represented by, for example, the general formula [V]

(In the formula, ring A, ring B, R ¹ , R ² , R ^3a and R ^3b have the same meaning as described above.)
Or a salt thereof and a general formula [VI]

(In the formula, n has the same meaning as described above.)
It can manufacture by making it react with the compound shown by presence of a base.

  These [Method A] to [Method C] can be carried out as follows.

[Method A]
In this production method, compound [II] can be carried out in a suitable solvent in the presence of an oxidizing agent. Examples of the oxidizing agent include 3-chloroperbenzoic acid, peracetic acid, sodium periodate, oxone and the like. As the solvent, any solvent can be used as long as it does not adversely influence the reaction. For example, dichloromethane, chloroform, acetonitrile, dimethoxyethane, tetrahydrofuran, water and the like can be appropriately used. This reaction can be carried out, for example, at −80 ° C. to 150 ° C., preferably 0 ° C. to 50 ° C.

[Method B]
The reaction of compound [III] and compound [IV] can be carried out in a suitable solvent in the presence of a urea agent. As a urea agent, the formula:

(Wherein W ¹ and W ² are the same or different and represent a leaving group.)
As shown in FIG. W ¹ and W ² are the same or different and include imidazolyl group, halogen atom or phenoxy group. Specifically, those such as 1,1′-carbonyldiimidazole and phosgene are preferred, and for example, carbonyl dihalides such as 1,1′-carbonyldiimidazole, triphosgene or phosgene can be used. As the solvent, any solvent can be used as long as it does not adversely influence the reaction. For example, acetonitrile, dichloromethane, tetrahydrofuran and the like can be appropriately used. This reaction can be carried out, for example, at 0 ° C. to 80 ° C., preferably 0 ° C. to 50 ° C.

  Further, this reaction includes compound [III], urea agent, formula

(W ¹ and W ^{2 in the} formula have the same meaning as described above.)
To give a general formula [VII]

(In the formula, ring A, R ¹ and W ² have the same meaning as described above.)
Then, compound [VII] is led to its reactive derivative and reacted with compound [IV], or compound [IV] and a urea agent, formula

(W ¹ and W ² have the same meaning as above)
To give a general formula [VIII]

(In the formula, ring B, R ² , R ^3a , R ^3b and W ² have the same meaning as described above.)
Then, compound [I] can also be produced by introducing compound [VIII] into its reactive derivative and reacting with compound [III].

As the reactive derivative, for example, in compound [VII] or compound [VIII], W ² can be represented by the formula

And compounds derived from groups such as

  The reaction of compound [III] or compound [IV] and a urea agent can be carried out, for example, at 0 ° C. to 80 ° C., preferably 0 ° C. to 50 ° C. As the solvent, any solvent can be used as long as it does not adversely influence the reaction. For example, acetonitrile, dichloromethane, tetrahydrofuran and the like can be appropriately used.

  The reaction leading compound [VII] or compound [VIII] to its reactive derivative is carried out using a reactive inducer such as methyl iodide, for example, 0 ° C. to 80 ° C., preferably 0 ° C. to 50 ° C. Can be implemented. As the solvent, any solvent can be used as long as it does not adversely influence the reaction. For example, acetonitrile, dichloromethane, tetrahydrofuran and the like can be appropriately used.

  The reaction of each reactive derivative with compound [III] or compound [IV] can be carried out in the presence of a base, for example, at 0 ° C. to 80 ° C., preferably 0 ° C. to 50 ° C. As the base, for example, triethylamine can be used, and any solvent can be used as long as it does not adversely affect the reaction. For example, toluene, acetonitrile, dichloromethane, tetrahydrofuran and the like can be used. It can be used as appropriate.

[Method C]
In this production method, the reaction of compound [V] or a salt thereof and compound [VI] can be carried out in a suitable solvent in the presence of a base. Examples of the base include organic bases such as triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 1,8-diazabicyclo [5,4,0] undec-7-ene, or potassium carbonate, sodium carbonate, cesium carbonate, water Examples thereof include inorganic bases such as sodium oxide, potassium hydroxide, sodium methoxide, potassium tert-butoxide and the like. Any solvent can be used as long as it does not adversely affect the reaction. For example, methanol, ethanol, isopropanol, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, ethyl acetate A solvent such as toluene, a mixed solvent thereof, a mixed solvent of these solvents and water, or the like can be used as appropriate. Examples of the salt of compound [V] include inorganic acid salts such as hydrochloride, hydrobromide and sulfate, methanesulfonate, p-toluenesulfonate, acetate, carbonate, trifluoroacetate and the like. These organic acid salts can be used as appropriate. This reaction can be carried out, for example, at 10 ° C to heating under reflux, preferably at 50 ° C to 120 ° C.

The general formula [IX]:

(In the formula, ring A, ring B, R ¹ , R ² , R ^3a and R ^3b have the same meaning as described above.)
Or an optical isomer thereof can be produced by reacting according to the method described in International Publication No. 2003/099787 pamphlet.

  Compound [II] can be carried out by subjecting compound [IX] or a salt thereof and thiomorpholine to a reductive amination reaction in an appropriate solvent. This reductive amination reaction can be carried out under acidic conditions by hydrogenation with a reducing agent such as sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride or a reduction catalyst such as palladium. Any solvent can be used as long as it does not adversely influence the reaction. For example, dichloromethane, acetic acid, ethanol, methanol and the like can be appropriately used. As the salt of compound [IX], hydrochloride, acetate, etc. can be used as appropriate. This reaction can be carried out, for example, at −10 ° C. to 80 ° C., preferably 0 ° C. to 30 ° C.

Further, the general formula [X]:

(Wherein R ⁴ represents a hydrogen atom or an amino-protecting group, and rings A and R ¹ have the same meaning as described above.)
Or an optical isomer thereof can be produced by reacting according to the method described in International Publication No. 2002/032867 pamphlet.

Examples of the protecting group for the amino group of R ⁴ include an alkoxycarbonyl group such as a tert-butoxycarbonyl group and an arylalkoxycarbonyl group such as a benzyloxycarbonyl group.

Compound [III] is obtained, for example, by subjecting compound [X] or a salt thereof and thiomorpholine to a reductive amination reaction in a suitable solvent, and when R ⁴ is a protecting group for an amino group, Can be carried out by removing. This reductive amination reaction can be carried out under acidic conditions by hydrogenation with a reducing agent such as sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride or a reduction catalyst such as palladium. Any solvent can be used as long as it does not adversely influence the reaction. For example, dichloromethane, acetic acid, ethanol, methanol and the like can be appropriately used. This reaction can be carried out, for example, at −10 ° C. to 80 ° C., preferably 0 ° C. to 30 ° C. The removal of the amino protecting group can be carried out by a conventional method.

Furthermore, the general formula [XI]:

(In the formula, ring A, ring B, R ¹ , R ² , R ^3a and R ^3b have the same meaning as described above.)
Or an optical isomer thereof can be produced by reacting according to the method described in International Publication No. 2003/099787 pamphlet.

Further, the general formula [XII]:

(In the formula, ring A, ring B, R ¹ , R ² , R ^3a and R ^3b have the same meaning as described above.)
Or an optical isomer thereof can be produced by reacting according to the method described in International Publication No. 2003/099787 pamphlet.

  Furthermore, the compound [III] is prepared according to the method described in the above [Method C], for example, the general formula [XIII]:

(In the formula, ring A, R ¹ and R ⁴ have the same meaning as described above.)
Or a salt thereof and a general formula [VI]

(In the formula, n has the same meaning as described above.)
It can manufacture by making it react with the compound shown by presence of a base.

  Furthermore, in the production of the compound which is the active ingredient of the present invention and the compound used in the present invention, when the raw material compound or each intermediate compound has a functional group, in addition to those described above, An appropriate protecting group is introduced into the group, and if not necessary, these protecting groups may be appropriately removed.

  In this specification, the alkyl group is, for example, a straight chain or branched chain having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, and an isopentyl group. An alkyl group, preferably having 1 to 4 carbon atoms. An alkenyl group means, for example, a straight or branched alkenyl group having 2 to 7 carbon atoms, such as a vinyl group, aryl group, propenyl group, isopropenyl group, etc., preferably having 2 to 5 carbon atoms. To do. The alkoxy group means, for example, a linear or branched alkoxy group having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, or a butoxy group, and preferably 1 to 4 carbon atoms. An alkanoyl group means, for example, a linear or branched alkanoyl group having 1 to 6 carbon atoms such as formyl group, acetyl group, propionyl group, butyryl group, valeryl group, tert-butylcarbonyl group, etc. And preferably means having 1 to 4 carbon atoms. The cycloalkyl group means, for example, a cycloalkyl group having 3 to 8 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and preferably 3 carbon atoms. Means ~ 6. Furthermore, examples of the halogen atom include chlorine, bromine, fluorine, and iodine.

Experimental Example 1 Neurokinin-1 (NK1) receptor binding inhibitory activity According to the method described in European Journal of Pharmacology Vol.254, pp. 221-227 (1994), IM-9 cells (4 × 10 ⁶ cell / tube) is 0.3 nM [ ³ H] (Sar ⁹ , Met ¹¹ (O ₂ )) Substance P (Kd value: 0.17 nM) and 10 nM of the sample compound and 150 mM NaCl, 3 mM In 0.5 ml of 50 mM Tris-HCl (pH 7.4, 25 ° C.) containing MnCl ₂ , 40 μg / ml bacitracin, 4 μg / ml leupeptin, 4 μg / ml chymostatin, 4 μg / ml phosphoramidon, 0.02% bovine serum albumin 60 minutes at room temperature It was. Suction filtered through a GF / C glass filter pretreated with 0.3% polyethyleneimine, washed twice with 3 ml of ice-cold reaction buffer containing no bovine serum albumin and various protease inhibitors, and filtered with a liquid scintillation counter The upper radioactivity (dpm) was measured. The specific binding amount is obtained by subtracting the non-specific binding amount (L-703606 (2 μM) having NK1 receptor antagonistic action) from the total binding amount, and the inhibition rate for the specific binding of the labeled ligand of the sample compound 10 nM is calculated. did.

  The results were as shown in Table A below.

Experiment 2 Effect on Neurokinin-1 Receptor Agonist Induced Behavior According to the method described in European Journal of Pharmacology 265, 179-183 (1994), male gerbil LSC Co., Ltd .: 40-80 g) was orally administered 1 mg / kg of the test drug. One hour after oral administration, under halothane anesthesia, GR73632 (5 pmol / 5 μl / head), an NK1 receptor agonist dissolved in distilled water at a depth of 1 mm and 4.5 mm in the side of the head bull bear, was injected into the ventricle. Administered. After intraventricular administration, the gerbil was moved to the observation gauge, and the time during which foot tapping was caused for 5 minutes after restoration of the right-angle reflex was measured. The inhibition rate (%) of foot tapping of the test drug was calculated by the following formula.
Inhibition rate of foot tapping (%) = {1− (tapping time in administration of test drug) / (tapping time in administration of solvent)} × 100
The results were as shown in Table B below.

  As is apparent from Table B, it can be seen that the compound which is the active ingredient of the present invention has a high ability to migrate to the center.

Experimental Example 3 Action on Frequent Urination According to the method described in Journal of Urology, Volume 155, No. 1, pp. 355-360 (1996), female guinea pigs were subcutaneously administered with urethane (1.2 g). / Kg), anesthesia was induced and the dorsal position was fixed, and then the lower abdomen was incised through the midline to expose the bladder and urethra. A cannula was inserted into both ureters to ensure a urinary tract. A cannula was inserted into the bladder through an 18G needle from the top of the bladder toward the lumen and fixed. The cannula was connected to a three-way stopcock, physiological saline was continuously infused from one end (room temperature, 12 ml / hr), and the intravesical pressure was measured from the other end. A urine collection tube was placed at the mouth of the external urethra, and urine output was measured by receiving urine in a container connected to an isotonic transducer. Further, a cannula for intraduodenal administration was inserted into the duodenum via a 22G injection needle and fixed, and then the lower abdomen was sutured. The neck was further dissected and a cannula was inserted into the trachea and right carotid artery. A continuous infusion of physiological saline was performed every 30 minutes, and parameters of micturition kinetics were measured. After the urination dynamics became stable, the saline was replaced with a physiological saline solution containing 0.1% acetic acid, and the urination dynamics were similarly observed. After obtaining the pre-drug value, the compound of Production Example 1 (0.3 mg / kg) was administered into the duodenum, and the increase in bladder capacity by the compound was evaluated as a percentage of the pre-dose value.

  As a result, the administration of the compound of Production Example 1 increased the bladder capacity by 60.3%. Therefore, it can be seen that the compound which is an active ingredient of the present invention has a strong bladder capacity increasing action.

Production Example 1
4- (S)-[1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R)-(4-fluoro-2- To a solution of 90 mg of methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine in 2 ml of dichloromethane were added 0.02 ml of methanesulfonic acid and 105 mg of metachloroperbenzoic acid, and the mixture was stirred at room temperature for 3 hours. A sodium thiosulfate aqueous solution was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Water and chloroform were added, liquid separation was performed, and the aqueous layer was extracted again with chloroform. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (n-hexane: ethyl acetate = 3: 1), followed by silica gel column chromatography (chloroform: ethyl acetate = 3: 1) to obtain the following Table 1. 1,1-dioxo-4- (S)-[1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R) 44 mg of (4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine was obtained.

Production Example 2-6
The corresponding starting materials were used and treated in the same manner as in Production Example 1 to obtain the compounds shown in Tables 1 and 2 below.

Production Example 7
4- (S)-[1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R)-(4-fluoro-2- Methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine 80 mg of dichloromethane solution (0.034 ml) was added dropwise to dichloromethane solution (5 ml), and then metachloroperbenzoic acid (70%) (33 mg) was added at -10 ° C. And stirred for 1 hour. A sodium hydrogen carbonate aqueous solution and dichloromethane were added to the reaction solution, followed by liquid separation. The obtained organic layer was dried over sodium sulfate and purified by silica gel column chromatography (chloroform: methanol = 19: 1). This was freeze-dried with tert-butanol to give 4- (S)-[1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl}-described in Table 2 below. 50 mg of N-methyl] -2- (R)-(4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] -1-oxothiomorpholine was obtained.

Production Example 8
(2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-tert-butoxycarbonylamino-2- (4 -Fluoro-2-methylphenyl) piperidine (11.3 g) in 1,4-dioxane (15 ml) was added with 4 M hydrochloric acid (1,4-dioxane solution) (45 ml) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and further dried in vacuo. 3 g of divinylsulfone and 5.1 g of triethylamine were added to a 50 ml solution of the residue in ethanol, and the mixture was stirred for 2 hours while heating under reflux. The reaction solution was concentrated and crystallized with diisopropyl ether to obtain 10.3 g of the same compound as described in Production Example 1.

Reference example 1
To 60 ml of a tetrahydrofuran solution of 3.91 g of N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methylamine was added 2.34 g of 1,1′-carbonyldiimidazole, and the mixture was heated to 40 ° C. And stirred overnight. After evaporating the solvent from the reaction solution, ethyl acetate was added, and the entire organic layer was washed with water and saturated brine and dried, and then the solvent was evaporated. The obtained residue was crystallized from diisopropyl ether and collected by filtration. The obtained white crystals were dissolved in 60 ml of acetonitrile, added with 3.4 ml of methyl iodide and reacted at 60 ° C. for 2 hours, and then the solvent was distilled off. The residue was dissolved in dichloromethane (40 ml). Under ice cooling, 2- (4-fluoro-2-methylphenyl) -4,4-dimethoxypiperidine (3.47 g) and triethylamine (3.82 ml) were added, and the mixture was stirred overnight at room temperature. The reaction solution was poured into water and separated, and the aqueous layer was extracted with dichloromethane. All organic layers were washed with water and saturated brine, dried and evaporated. The residue was dissolved in 90 ml of tetrahydrofuran, 30 ml of 1M sulfuric acid aqueous solution was added under ice cooling, and the mixture was stirred at room temperature for 5 hours. After adjusting the pH to 8-9 with 1M aqueous sodium hydroxide solution, tetrahydrofuran was distilled off, water and ethyl acetate were added to the residue for liquid separation, and the aqueous layer was extracted with ethyl acetate. All organic layers were washed with water and saturated brine, dried and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give (2R) -1- [N- {1- (S)-(3,5-bistritene] described in Table 3 below. 2.12 g of fluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine was obtained.

Reference Example 2-3
The corresponding starting materials were used and treated in the same manner as in Reference Example 1 to obtain the compounds shown in Table 3 below.

Reference example 4
(2R) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 -To a solution of oxopiperidine (504 mg), thiomorpholine (155 mg) and acetic acid (0.057 ml) in dichloromethane (15 ml) was added sodium triacetoxyborohydride (446 mg), and the mixture was stirred at room temperature for 16 hours. To the reaction solution, 52 mg of thiomorpholine and 112 mg of sodium triacetoxyborohydride were added, and the mixture was further stirred at room temperature for 3 hours. Water and chloroform were added, liquid separation was performed, and the aqueous layer was extracted again with chloroform. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (n-hexane: ethyl acetate = 3: 1), followed by silica gel column chromatography (chloroform: ethyl acetate = 3: 1) to obtain the following Table 3. (A) 4- (S)-[2- (R)-(4-fluoro-2-methylphenyl) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ) Ethyl} -N-methyl] aminocarbonylpiperidin-4-yl] thiomorpholine and 92b and (b) 4- (R)-[2- (R)-(4-fluoro-2-methylphenyl) -1- [ 164 mg of N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonylpiperidin-4-yl] thiomorpholine was obtained.

Reference Example 5-6
The corresponding starting materials were used and treated in the same manner as in Reference Example 4 to obtain the compounds shown in Table 4 below.

Reference Example 7
(2R, 4R) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-bromo-2- (4-fluoro-2 -Methylphenyl) piperidine 280 mg of N, N-dimethylformamide solution was added with 0.2 ml of thiomorpholine and stirred at 90 ° C. for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 3) to obtain 80 mg of the same compound as described in Reference Example 4 (a).

  The compound which is an active ingredient of the present invention has an excellent tachykinin receptor antagonistic action. In addition, the compound which is an active ingredient of the present invention is highly safe and excellent in terms of absorbability, intracerebral transferability, metabolic stability, blood concentration, sustainability, and the like, and thus exhibits excellent medicinal effects.

Claims (6)

Formula [I]

(In the formula, ring A represents a benzene ring which may have a substituent.
Ring B represents a benzene ring which may have a substituent.
R ¹ is a hydrogen atom, a hydroxyl group which may have a substituent, an amino group which may have a substituent, an alkyl group which may have a substituent, or a carbonyl group which has a substituent. Or represents a halogen atom.
R ² represents a hydrogen atom or an alkyl group which may have a substituent.
R ^3a and R ^3b are the same or different and each represents a hydrogen atom or an alkyl group which may have a substituent, or a group which is bonded at a terminal to form an alkylene group.
n represents an integer of 1 or 2. )
A pharmaceutical composition comprising as an active ingredient a thiomorpholine compound represented by the formula or a pharmacologically acceptable salt thereof. Ring A has the formula:

Wherein A ¹ represents an alkyl group, A ² represents a halogen atom, and ring B is represented by the formula:

Wherein B ¹ represents a trihalogenoalkyl group, B ² represents a trihalogenoalkyl group, R ¹ represents a hydrogen atom, R ² represents an alkyl group, and R ^3a and R ^3b represent A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient, which are the same or different and each is a hydrogen atom or an alkyl group. A pharmaceutical composition comprising a compound selected from the following (a) to (g) or a pharmaceutically acceptable salt thereof as an active ingredient.
(A) 1,1-dioxo-4- (S)-[1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R )-(4-Fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,
(B) 1,1-dioxo-4- (R)-[1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R )-(4-Fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,
(C) 1,1-dioxo-4- (S)-[1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R )-(4-Fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,
(D) 1,1-dioxo-4- (R)-[1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R )-(4-Fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,
(E) 1,1-dioxo-4- (S)-[1- {N- (3,5-bistrifluoromethylphenyl) methyl-N-methyl} -2- (R)-(4-fluoro-2 -Methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,
(F) 1,1-dioxo-4- (R)-[1- {N- (3,5-bistrifluoromethylphenyl) methyl-N-methyl} -2- (R)-(4-fluoro-2 -Methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine and (g) 4- (S)-[1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl}- N-methyl] -2- (R)-(4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] -1-oxothiomorpholine. The pharmaceutical composition according to any one of claims 1 to 3, which is a tachykinin receptor antagonist. It is a prophylactic / therapeutic agent for diseases selected from inflammation, allergic diseases, pain, migraine, neuralgia, pruritus, cough, central nervous system diseases, digestive system diseases, nausea, vomiting, abnormal urination, cardiovascular diseases and immune abnormalities. The pharmaceutical composition according to any one of claims 1 to 3. The pharmaceutical composition according to claim 5, wherein the disease is abnormal urination.