WO2003035641A1

WO2003035641A1 - Novel carbamoylpyrrolidone derivative

Info

Publication number: WO2003035641A1
Application number: PCT/JP2002/010877
Authority: WO
Inventors: Toshisada Yano; Shunji Shinohara; Chie Takeyama
Original assignee: Shionogi & Co., Ltd.
Priority date: 2001-10-22
Filing date: 2002-10-21
Publication date: 2003-05-01
Also published as: JPWO2003035641A1

Abstract

A compound represented by the formula (I) (wherein A represents -NR1-(CH2)m- (R1 is hydrogen or lower alkyl and m is an integer of 2 to 5 or a single bond); Z1 and Z2 each independently is hydrogen or a substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkenyl, halogeno, halogenated lower alkyl, halogenated lower alkoxy, hydroxy, carboxy, and nitro; and n is an integer of 1 to 3). It has an antagonistic effect on an NMDA receptor, and is hence useful as a remedy for brain infarction in the acute stage, remedy for chronic nerve degeneration diseases, analgesic, etc.

Description

Specification

New field of rubamoylpyrrolidone derivatives

TECHNICAL FIELD The present invention relates to a novel carpamoylpyrrolidone derivative having an antagonistic effect on an NMD A receptor, which is a kind of glutamate receptor of central nervous cells, particularly an NR1 / NR2B complex receptor. Background

Amino acids such as L-glutamic acid and L-aspartic acid are important for neuronal activation as neurotransmitters in the central nervous system. However, the extracellular accumulation of these excitatory amino acids induces excessive stimulation of nerve cells, causing various neurological diseases such as Parkinson's disease, senile dementia, Huntington's chorea, and epilepsy, and It is thought to cause mental and motor deficits such as those seen during hypoxia, hypoxemia, hypoglycemia, and head or spinal cord injury (McGeer et al., Nature, 263, 517- 519 (1976), Simon et al. Science, 226, 850-852 (1984), Wieloch, Science, 230, 681-683 (1985), Faden et al., Science, 244, 798-800 (1989), Turski et al., Nature , 349, 414-418 (1991)).

It is known that the activity of the above-mentioned excitatory amino acids on central nervous cells acts via the glutamate receptor present on the nerve cells. Therefore, a substance that antagonizes the binding of the above-mentioned excitatory amino acid to such a receptor is useful as a therapeutic drug for the above-mentioned diseases and symptoms, for example, an antiepileptic drug, an ischemic brain injury preventive drug, and an antiparkinson drug. It is believed that. In particular, glutamic acid is released in large amounts by cerebral ischemia such as cerebral infarction, so antagonists to the glutamic acid receptor are used as a therapeutic drug for acute phase of cerebral infarction and for chronic gods such as Alzheimer's disease.絰 It is considered to be useful as a therapeutic agent for degenerative diseases.

The glutamate receptors are classified into ion channel type and metabolic type, and the ion channel type is further classified into three types based on selectivity for agonists. These are the N-methyl-D-aspartate (NMDA) receptor, No 3- (3-hydroxy-15-methylisoxazoyl-41-yl) is called propanoic acid (AMP A) receptor and force rice receptor.

Of these, the NMD A receptor is selectively activated by agonists such as glutamate, NMDA, and ibotenic acid. This strong stimulation of the NMD A receptor causes a large amount of calcium ions to enter the nerve cells, which is thought to be one of the causes of neurodegenerative cell death.

In recent years, the gene for the NMD A receptor has been cloned from rat and mouse brain, respectively, and it has been revealed that the NMD A receptor is composed of two subunits, NR1 and NR2 (Katsuwada et al. Nature, 358, 36-41 (1992), Mega et al., Nature, 357, 70-74 (1992)). There are four additional subfamilies (NR2A, 2B, 2C, 2D) in the NR2 subunit (Monyer et al., Science, 256, 1217-1221 (1992), Yamazaki et al., FEBS Lett., 300 , 39-45 (1992)). The role of each of the NR 2 subfamilies is gradually becoming clearer, using the knockout mouse of the NR 2 subfamily. The NR1ZNR2A complex receptor is involved in memory formation and learning acquisition (Sakimura et al., Nature, 373, 151-155 (1995)). It is said to be involved (Di X, Bullock R et al., Stroke, 28, 2244-2251 (1997)).

Furthermore, among the NMD A receptors, especially the NR 2 B receptor has also been reported to be associated with analgesic effects, and its antagonists are expected to be analgesics with few side effects (TRENDS in Pharmacological Sciences Vol.22 No.12 December 2001) o

As NMD A receptor antagonists, 1) drugs that competitively bind to agonist, such as glutamate-NMD A, in all subfamilies of NR1ZNR2 complex receptors (hereinafter, referred to as Competitive NMD A antagonists, eg: D-2-amino-5-phosphonovaleric acid) or 2) In the ion channel at the NMD A receptor: Glutamic acid or: NMD A to the PCP (phencyclidine) binding site Drugs that bind non-competitively irrespective of agonist and suppress calcium ion influx into nerve cells (hereinafter referred to as non-competitive NMD A antagonists, eg, MK-801) Are known.

JP-A-113-1155, JP-A-41-21059 and JP-A-61-1968 disclose carpamoylpyrroli useful as an anti-dementia drug, a psychotropic drug and an anti-allergic drug. Don derivatives are described, but no antagonism to the NMDA receptor is described. Disclosure of the invention

However, since competitive NMD A receptor antagonists also antagonize the NR1 / NR 2A complex receptor, long-term drug use such as Alzheimer's disease causes a decrease in learning ability and memory formation. Is concerned. In the case of non-competitive NMDA receptor antagonists, side effects such as psychiatric disorders occur by binding to the PCP receptor (Nishikawa et al., Neuropsychiacology, 13, 865-876 (1991)). In addition, sufficient drug efficacy cannot be expected in clinical practice. Therefore, there is a need for a clinically useful NMDA receptor antagonist that preferably has no such side effects.

Thus, the present inventors have conducted intensive studies, and as a result, it has been found that certain rubamoylpyrrolidone derivatives exhibit NMDA receptor antagonism, particularly selective and strong antagonism against the NR1 / NR2B complex receptor. The present inventors have found that they are useful as a therapeutic agent for acute phase of cerebral infarction, a therapeutic agent for chronic neurodegenerative diseases, or an analgesic, and completed the invention described below. Formula (I)

(Where

Α is one NR ¹ — (CH ₂ ) m— (R ¹ is hydrogen or lower alkyl; m is an integer of 2 to 5) or a single bond;

Z ¹ and Z ² are each independently hydrogen, lower alkyl, lower alkoxy, lower A substituent selected from the group consisting of alkenyl, halogen, halogenated lower alkyl, halogenated lower alkoxy, hydroxy, carboxy and nitro; n represents an integer of 1-3. )

Or a pharmaceutically acceptable salt thereof, a prodrug thereof or a solvate thereof.

2. The compound according to 1 above, wherein A is -NR ¹ — (CH ₂ ) m- (wherein each symbol is as defined above), a pharmaceutically acceptable salt thereof, a prodrug thereof or a solvent thereof. Japanese food.

3. The compound according to the above 1, wherein A is a single bond, a pharmaceutically acceptable salt thereof, a prodrug thereof or a solvate thereof.

4. Z ¹ is hydrogen, and Z ² is a substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkenyl, halogen, lower alkyl halide, lower alkoxy halide, hydroxy, carboxy, and nitro The compound according to the above 1, a pharmaceutically acceptable salt thereof, a prodrug thereof or a solvate thereof. 5. The above item 4, wherein Z ¹ is hydrogen and Z ² is a substituent selected from the group consisting of methyl, butyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy and hydroxy. Or a pharmaceutically acceptable salt thereof, a prodrug thereof or a solvate thereof.

6. A is —NR ¹ — (CH ₂ ) m— (where R ¹ is hydrogen or lower alkyl; m is 2 or 3); n is 1; Z ¹ is hydrogen; Z ² is lower alkyl, lower alkoxy A compound selected from the group consisting of: lower alkenyl, halogen, lower alkyl halide, lower alkoxylated halogen, hydroxy, carboxy and nitro; the compound according to 1 above, or a pharmaceutically acceptable salt thereof, The prodrugs or their solvates.

7. A is a single bond; n is 1; Z ¹ is hydrogen; Z ² is from the group consisting of lower alkyl, lower alkoxy, lower alkenyl, halogen, halogenated lower alkyl, halogenated lower alkoxy, hydroxy, carboxy and nitro The compound according to the above 1, which is a selected substituent, a pharmaceutically acceptable salt thereof, a prodrug thereof or a solvate thereof. TJP02 / 10877

8. A pharmaceutical composition comprising the compound according to any one of the above 1 to 7, a pharmaceutically acceptable salt thereof, a prodrug thereof or a solvate thereof.

9. The pharmaceutical composition according to the above item 8, which is an NMD A receptor antagonist.

10. The pharmaceutical composition according to the above 9, which is an antagonist of a complex receptor of NR1 and NR2B, which is a subunit of NMD A receptor.

1 1. The pharmaceutical composition according to the above item 8, for suppressing neuronal degeneration due to NMD A and / or hypoxia.

12. The pharmaceutical composition according to the above item 8, which is a therapeutic agent for acute phase of cerebral infarction or a therapeutic agent for chronic neurodegenerative disease.

1 3. The pharmaceutical composition according to the above 8, which is an analgesic.

14. Prevention of a disease attributable to the NMD A receptor, which comprises administering the compound according to any one of the above 1 to 7, a pharmaceutically acceptable salt thereof, a mouth drag thereof or a solvate thereof. Or treatment method.

15. The compound according to any one of the above 1 to 7, a pharmaceutically acceptable salt thereof, a prodrug thereof, or a compound thereof for the manufacture of a medicament for preventing or treating a disease caused by an NMD A receptor. Use of solvates. BEST MODE FOR CARRYING OUT THE INVENTION

The definition of each group of the compound (I) of the present invention will be explained. Each term, either alone or in combination, has the following meaning.

Lower alkyl includes straight-chain or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, η-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, Examples thereof include sec-butyl, n-pentyl, i-pentyl, neo-pentyl, tert-pentyl, n-pentyl, i-pentyl, neo-pentyl, tert-pentyl, n-hexyl and the like. It is preferably an alkyl having 1 to 4 carbon atoms, particularly methyl or ethyl. The lower alkoxy includes the oxy bonded to the lower alkyl, and examples thereof include methoxy, ethoxy, i-propoxy, tert-butoxy, pentyloxy, and hexyloxy. Preferred is methoxy.

Lower alkenyl includes straight-chain or branched alkenyl having 2 to 6 carbon atoms, P0210877

Examples include vinyl, aryl, i-propenyl, 2-butenyl, 3-pentenyl, 2-hexenyl and the like. Preferably, it is alkenyl having 2 to 4 carbon atoms.

Halogen includes fluorine, chlorine, bromine and iodine. Preferably, it is fluorine or chlorine.

Z ¹ and Z ² are the same or different and are selected from the group consisting of chromium, lower alkyl, lower alkoxy, lower alkenyl, halogen, lower alkyl halide, lower alkoxy halide, hydroxy, carboxy and nitro The group is exemplified. These may be present at any substitutable position on the benzene. Preferably, these substituents include hydrogen, methyl, butyl, methoxy, fluoro, chloro, promo, trifluoromethyl, trifluoromethoxy and hydroxy.

Preferably a substituent Z ¹ is selected from hydrogen, Z ² is lower alkyl, lower alkoxy, lower alkenyl, halogen, halogenated lower alkyl, from the group consisting of halogenated lower alkoxy and human Doroki sheet. Particularly preferably, Z ¹ is hydrogen and Z ² is a substituent selected from the group consisting of methyl, t-butyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy and hydroxy. m is an integer of 2 to 5, preferably 2 or 3. n is an integer of 1 to 3, and is preferably 1. More preferred compound (I) is as follows.

1) A is—NR ¹ — (CH ₂ ) m— (where R ¹ is hydrogen or lower alkyl; m− is 2 or 3); n is 1; Z ¹ is hydrogen; Z ² is lower alkyl, lower When the substituent is selected from the group consisting of alkoxy, lower alkenyl, halogen, lower alkyl halide, lower alkoxy halide, hydroxy, carboxy and nitro. Particularly preferred is the case where Z ² is methyl, t-butyl, methoxy, F, C 1, −0 CF 3 or the like.

2) A is a single bond; n is 1; Z ¹ is hydrogen; Z ² is a lower alkyl, lower alkoxy, lower alkenyl, halogen, halogenated lower alkyl, halogenated lower alkoxy shea, hydroxy, carboxy and nitro Selected substituent TJP02 / 10877

If Particularly preferably, Z ² is methyl, t one-butyl, main butoxy, F, C l, is the case for such -0 C _3. The typical production method of compound (I) is illustrated below.

(1) When A = — NR ¹ — (CH ₂ ) m—

(Method A)

N people ⁰

(Wherein, X is a leaving group (eg, halogen, etc.); other symbols are as defined above.) The compound (II) is reacted with the compound (III) in the presence of a base, if desired, to give a compound

Obtain (1-1). As the base, carbonates _{_{_{(K 2 C0 3, Na 2}}} C0 3 , etc.) or NaOH, 3 tertiary Amin (Example: Et ₃ N) and the like can be used. KI may be used in combination. As a solvent, acetonitrile, dimethylformamide (DMF), dimethylsulfoxide (DMS0), tetrahydrofuran (THF) and the like can be used. The reaction temperature is usually about 10 to 200 ° C, preferably room temperature to about 140 ° C, and the reaction time is several hours to several tens hours, preferably about 1 to 20 hours, more preferably about 3 to 15 hours. It is. Compounds (II) and (III) may be synthesized by a well-known reaction or commercially available products may be used. (Method B)

(Wherein X is a leaving group (eg, phenyloxy and the like); other symbols are as defined above). Compound (IV) is reacted with compound (V) in the presence of a base, if desired, to give compound (I— 1) get. As the base, carbonates _{_{_{(K 2 C0 3, Na 2}}} C0 3 , etc.) or NaOH, 3 tertiary Amin (Example: Et ₃ ii) and the like can be used. As the solvent, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMS 0), tetrahydrofuran (THF) and the like can be used. The reaction temperature is generally about 10 to 200 ° C, preferably room temperature to about 140 ° C, and the reaction time is several hours to several tens hours, preferably about 1 to 20 hours, more preferably about 3 to 1 hour. 5 hours. Compounds (IV) and (V) may be synthesized by well-known reactions or commercially available products may be used.

(2) A = single bond

(t-2) (wherein, X is a leaving group (eg, phenyloxy, etc.); other symbols are as defined above) The compound (IV) is reacted with the compound (III) in the presence of a base, if desired, to give a compound (1-2). As the base, carbonates _{_{(K 2 C 0 3, Na}} 2 C 0 3 , etc.) and N A_〇 H, 3 tertiary Amin (Example: Et ₃ N) and the like can be used. As the solvent, acetonitrile, dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF) and the like can be used. The reaction temperature is generally about 10 to 200 ° C., preferably room temperature to about 14 CTC, and the reaction time is several hours to several tens of hours, preferably about 1 to 20 hours, more preferably about 3 to 20 hours. ~ 15 hours. Compounds (IV) and (III) may be synthesized by a well-known reaction, or a commercially available product may be used.

In addition, before any of the above reactions, if necessary, an appropriate protection reaction may be performed on the functional group according to a method well known to those skilled in the art, and a deprotection reaction may be performed after the reaction. Examples of the pharmaceutically acceptable salt of compound (I) include salts formed with inorganic acids, organic acids, inorganic bases and the like, and inner salts. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and examples of the organic acid include p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, maleic acid, and oxalic acid. An example is shown. Examples of the inorganic base include Na, K and the like. Compound (I) may be a solvate such as aqueous alcohol.

A prodrug is a derivative of a compound of the present invention that has a chemically or metabolically degradable group and is a compound that becomes a pharmaceutically active compound of the present invention in vivo by solvolysis or under physiological conditions. Methods for selecting and manufacturing appropriate prodrug derivatives are described in, for example, Design of Prodrugs,

Elsevier, Amsterdam 1985.

When the present compound has a hydroxyl group, a prodrug such as an acyloxy derivative produced by reacting a compound having a hydroxyl group with a suitable acyl halide or a suitable acid anhydride is exemplified. — 0 COC ₂ H ₅ , — OCO (t -B u), —〇 COC i ₅ H ₃ I-0 CO (m- CO ONa-

P h), one OCO CH ₂ CH ₂ CO ON a, one O CO CH (NH ₂ ) CH ₃ , one 0

COCH ₂ N (CH ₃ ) _{2 and the} like.

Compound (I) is useful as a medicament. In particular, since it has an NMD A receptor antagonistic effect, it is effective for various diseases caused by the receptor, such as chronic neurodegeneration. It is useful as a drug for treating diseases (eg, Parkinson's disease, senile dementia, Huntington's chorea), antiepileptic drug or analgesic. It is also effective as a therapeutic agent for acute phase of cerebral infarction because it is effective against neuronal degeneration caused by hypoxia.

Compound (I) can be orally or parenterally administered to animals including humans. Examples of dosage forms include granules, tablets, capsules, and injections. Upon formulation, various additives such as excipients, disintegrants, binders, lubricants, stabilizers, coloring agents, and coating agents can be used, if desired. The dosage varies depending on the age, body weight, condition and administration method of the subject, and is not particularly limited.However, in the case of oral administration per adult per day, it is generally about 20 mg to about 1000 mg, and parenteral administration is usually used. In this case, it is about 2 mg to about 100 mg.

Administration of compound (I) suppresses neuronal degeneration and chronic neurodegenerative diseases in cerebral infarction. The mechanism of action is as follows: (1) It acts as an antagonist to the NMDA receptor that is excessively generated during neurodegeneration and binds to NMDA glutamate, particularly the NR1 / NR2B complex receptor involved in neuronal degeneration. 2) It is thought that nerve cell degeneration is suppressed by the fact that ion channels in nerve cells do not open and calcium ions do not flow into nerve cells. In addition, since the more preferred compound of the present invention does not bind to the PCP receptor in the ion channel, it is considered that there is no side effect such as mental disorder. (Example)

Abbreviation Me: methyl, t-Bu: t-butyl

Example 1

2-oxopyrrolidine-one-potency ruponic acid {2- (4- (3,4-dichloropentyl)-4-hydroxypiperidine-1-1-yl-1-ethyl) -amide (3) DMF containing 2-oxopyrrolidine-one-potency ruponic acid (2-chloroethyl) amide (1) 1.lg, 4-hydroxy-14- (3,4-dichlorobenzyl) piperidine (2) 1.5 g The solution (15 mL) is stirred at 105 to 110 ° C for 10 hours in the presence of K ₂ C ₃ 1.59 g and potassium iodide 0.48 g. The reaction solution obtained is poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over M g S 0 _4, the solvent was distilled off under reduced pressure. The obtained oily residue was purified by silica gel chromatography (chloroform: methanol = 20/1 to: 10/1) to obtain (3) 1.92 g. The hydrochloride of this substance was recrystallized from methanol-isopropanol.

Elemental analysis (%): C19H25C12N303-HC1

Calculated values: C = 50.62, H = 5.81, N = 9.32, Cl = 23.59

Experimental values: 0 = 50.62, Η = 5.7β, Ν = 9 · 29, Cl = 23.47

_{NMR (CDCl 3) <5 pm} (300 MH Z) (FREE)

1.44-1.80 (4H, m), 2.030 (2H, quint, J = 7.8Hz), 2.28-2.76 (4H, m),

2.537 (2H, t, J = 6.3Hz), 2.604 (2H _; t, J = 8.lHz), 2.705 (2H, s),

3.409 (2H, q, J = 6.3Hz), 3.850 (2H, t, J = 6.9Hz), 7.039, 7.066 (IH, Abq,

J = 1.8Hz), 7.323 (IH, d, J = 1.8Hz), 7.360 (IH, d, J = 8.lHz), 8.63 (1H, brs)

The compounds of Examples 2 to 4 were synthesized according to the method of Example 1. The structural formula is shown below. Example 2

Compound 4

Elemental analysis (%): C20H29N3O3 · HC1

Calculated values: C = 60.67, Η = 7.64, Ν = 10 · 61, Cl = 8.95

Experimental value: C = 60.44, H = 7.66, N = 10.59, Cl = 8.72

_{NMR (CDCl 3) 5ppra (300} MH Z) (FREE)

1.46-1.80 (4H, m), 2.026 (2H, quint, J = 7.2Hz), 2.30-2.70 (4H, m), 2.326 (3H, s), 2.533 (2H, t, J = 6.3Hz) _; 2.605 (2H, t, J = 8.4Hz), 2.715 (2H, s), 3.416 (2H, q, J = 6.3Hz), 3.856 (2H, t, J = 7.5Hz), 7.082 (2H, d, J = 8.4Hz) _; 7.120 (2H, d, J = 8.4Hz), 8.63 (IH, brs)

Compound 5

Elemental analysis (%): C19H26C11N303

Calculated values: C = 54.81, H = 6.54, N = 10.09, Cl = 17.03

Experimental value: C = 54.77, Η = 6.20, Ν = 10 · 06, Cl = 16.52

_{NMR (CDCl 3) 5 ppm (} 300 MH Z) (FREE)

1.43- 1.80 (4H, m), 2.028 (2H, quint, J = 7.8Hz), 2.28-2.76 (4H, m),

2.534 (2H, t, J = 6.6Hz), 2.605 (2H, t, J = 8.1Hz), 2.723 (2H, s),

3.413 (2H, q, J = 6.6Hz), 3.854 (2H, t, J = 7.5Hz), 7.139 (2H, d, J = 8.4Hz) _; 7.273

(2H, d, J = 8.4Hz), 8.63 (IH, brs) Example 4

Compound 6

Elemental analysis (%): C23H35N303 · HCl

Calculated values: 0 = 63.07, H = 8.28, N = 9.59,

Experimental values: C = 62.78, H = 8.27, N = 9.52,

NMR (CD Cl ₃ ) d ppm (300 MH _Z ) (FREE)

1.310 (9H, s), 1.45- 1.85 (4H, m), 2.027 (2H, quint, J = 7.2Hz), 2.35-2.70 (4H, m),

2.541 (2H, t, J = 6.6Hz), 2.607 (2H, t, J = 8.4Hz), 2.724 (2H, s), JP02 / 10877

3.421 (2H, q, J = 6.6Hz), 3.859 (2H, t, J = 8.lHz), 7.129 (2H, d, J = 8.4Hz), 7.324 (2H, d, J = 8.4Hz), 8.63 (1H, brs) As a reference example, the compound of formula (I) where n = 0, that is, the following compound in which a piperidine ring and a benzene ring are directly bonded was synthesized. Reference example

Compound 7

Reference example 2

The following compounds were synthesized according to the method of Example 1.

Example 5

Compound 9

NMR (CDCl3) c5- ppm (300 MHZ) (Free) 1.50-1.88 (5H, m), 2.021 (2H, quint, J = 8.1Hz), 2.26-2.72 (4H, m), 2.530 (2H, t, J = 6.3Hz), 2.596 (2H, t, J = 8.1Hz), 2.800 (2H, s) 3.413 (2H, q, J = 6.6Hz) 3.845 (2H, t, J = 7.2Hz), 7.00-7.20 (4H, in) _; 8.55-8.73 (lH, m)

Elemental analysis (%): C20H29N303 · HC1

Calculated values: c = 60.67, H = 7.64, N = 10.61, C1 = 8.95

Experimental value: C = 60.51, H = 7.72, N = 10.51, C1 = 8.65

Compound 10

NMR (CDC13) c5- ppm (300 MHZ) (Free)

1.40- 1.84 (5H, m), 2.023 (2H, quint, J = 7.5Hz), 2.20-2.70 (4H, m), 2.532 (2H, t, J = 6.6Hz), 2.601 (2H, t, J = 8.1Hz), 2.715 (2H, s) 3.413 (2H, q, J = 6.3Hz) 3.851 (2H, t, J = 7.2Hz), 6.93-7.10 (3H, m), 7.189 (1H, t, J = 7.5Hz), 8.55-8.73 (lH, m)

Elemental analysis (%): C20H29N303-HC1

Calculated values: c = 60.67, H = 7.64, N = 10.61, C1 = 8.95

Experimental value: C = 60.58, H = 7.80, N = 10.46, C1 = 8.56 Example 7

Compound 1 1

NMR (CDC13) d ppm (300 MHZ) (Free)

1.44-1.80 (5H, m), 2.026 (2H, quint, J = 7.2Hz), 2.26- 2.70 (4H, m), 2.532 (2H, t, J = 6.3Hz), 2.603 (2H, t, J = 8.1Hz), 2.725 (2H, s) 3.41K2H, q, J = 6.3Hz) 3.851 (2H, t, J = 7.2Hz), 6.93-7.22 (4H, m), 8.52-8.75 (lH, m)

Elemental analysis (%): C19H26FN303 · HC1

Calculated values: c = 57.07, H = 6.81, N = 10.51, C1 = 8.87, F = 4.75

Experimental values: C = 57.09, H = 6.84, N = 10.32, C1 = 8.40, F = 4.39 Example 8

Compound 1 2

NMR (CDC13) ppm (300 MHZ) (Free)

1.20- 1.80 (5H, m), 2.029 (2H, quint, J = 7.8Hz), 2.28-2.70 (4H, m),

2.536 (2H, t, J = 6.6Hz), 2.603 (2H, t, J = 8.4Hz), 2.757 (2H, s)

3.412 (2H, q, J = 6.3Hz), 3.851 (2H, t, J = 7.2Hz), 7.143 (2H, d, J = 8.7Hz): 7.232 (2H, t, J = 8.7Hz), 8.50- 8.80 (lH, m)

Elemental analysis (%): C20H26F3N304 · HC1

Calculated values: C = 51.56, H = 5.84, N = 9.02, Cl = 7.61, F = 12.23

Experimental value: C = 51.47, H = 5.87, N = 9.00, Cl = 7.39, F = 12.10 Example 9

Compound 1 3

NMR (CDC13) 0-ppm (300 MHZ) (Free)

1.40-1.90 (5H, m), 2.031 (2H, quint, J = 7.5Hz), 2.22-2.75 (4H, m),

2.539 (2H, t, J = 6.3Hz), 2.607 (2H, t, J = 8.1Hz), 2.774 (2H, s)

3.415 (2H, q, J = 6.0Hz), 3.856 (2H, t, J = 7.2Hz), 7.04-7.20 (3H, m) 7.32K1H, t, J = 7.8Hz), 8.50- 8.80 (1H, m )

Elemental analysis (%): C20H26F3N304 · HC1 · 1 / 2H20

Calculated values: c = 50.58, H = 5.94, N = 8.85, Cl = 7.47, F = 12.00

Experimental value: C = 50.85, H = 5.85, N = 9.02, Cl = 7.42, F = 12.13 Example 10

Compound 1 4

NMR (CDC13) d ppm (300 MHZ) (Free)

1.44- 1.80 (4H, m), 2.025 (2H, quint, J = 7.8Hz), 2.26-2.75 (5H, m),

2.532 (2H, t, J = 6.6Hz), 2.602 (2H, t, J = 8.4Hz), 2.692 (2H, s)

3.413 (2H, q, J = 6.3Hz), 3.789 (2H, s), 3.852 (2H 3 t, J = 6.9Hz) 3 6.844 (2H, d, J = 8.7Hz),

7.114 (2H, d, J = 8.7Hz), 8.50-8.80 (lH, m)

Elemental analysis (%): C20H29N304 · HC1

Calculated values: c = 58.32, H = 7.34, N = 10.20, C1 = 8.61

Experimental value: C = 58.17, H = 7.33, N = 10.25, C1 = 8.24 Example 1 1

15 17

1- [4-Hydroxy-1- (4-methyl-1-benzyl) -piperidin-1 1-carbonyl] -pyrrolidine-1 2-one (17)

0.45 g of 2-oxopyrrolidine-1-carboxylic acid phenyl ester (15) and 0.45 g of 4- (4-methyl-benzyl) -piperidine-14-ol (16) are mixed and mixed in nitrogen gas at 100 ° C for 4.5. Stir for hours. The obtained reaction solution was purified by silica gel chromatography (ethyl acetate), and recrystallized from ethyl acetate diisopropyl ether to obtain 0.74 g of (17).

NMR (CDC13) (5 ppm (300 MHZ) (Free)

1.50- 1.90 (4H, m), 2.070 (2H, quint, J = 7.5Hz), 2.334 (3H, s), 2.466 (2H, t, J = 8.1Hz), 2.744 (2H, s), 3.10-4.25 (5H, m), 7.075 (2H, d, J = 8.1Hz), 7.133 (2H, d, J = 8.1Hz)

Elemental analysis (%): C18H24N203

Calculated values: c = 68.33, H = 7.65, N = 8.85,

Experimental value: C = 68.38, H = 7.74, N = 8.72, Example 1 2

Compound 1 8

The following compounds were synthesized according to the method of Example 11. TJP02 / 10877

Awake (CDC13) d-ppm (300 MHZ) (Free)

1.40-2.00 (4H, m), 2.071 (2H, quint, J = 7.5Hz), 2.461 (2H, t, J = 8.1Hz): 2.787 (2H, s), 3.10-4.30 (5H, m), 7.158 (2H, d, J 8.7Hz), 7.229 (2H, d, J 8.7Hz)

Compound 20

NMR (CDC13) 3 ppm (300 MHZ) (Free)

1.43-2.00 (6H, m), 2.077 (2H, quint, J = 7.5Hz), 2.20 ~ 2.70 (9H, m),

2.786 (2H, s), 2.973 (3H, s), 3.30-3.50 (2H, m), 3.718 (2H, t, J = 7.2 Hz) 7.00-7.20 (3H, m), 7.326 (lH, t, J = 7.8Hz)

Elemental analysis (%): C22H30F3N304 · HC1

Calculated values: c = 53.50, H = 6.33, N = 8.51, C1 = 7.18, F = 11.54

Experimental value: C = 53.14, H = 6.38, N = 8.48, C1 = 7.06, F = 11.31 Test example

Expression and electrophysiology of NMD A receptor subunit

The complementary DNA (cDNA) of the mouse NMD A receptor subunit was transcribed as type I into the messenger UNA (mRNA), and this mRNA was injected into African Megafrog oocytes. Three days after injection, NMD A was induced using a two-electrode membrane voltage clamp device. The inward current was recorded. The injection amount of mRNA was 12.5 / 12.5 ng corresponding to NR1 / NR2B per oocyte, and co-expression of subunits was performed. The oocytes were placed in a solution (compound concentration: 100 M) containing a test compound (compounds 4, 5, 7, 8), and the NMDA-induced inward current was recorded using a two-electrode voltage clamp device. The extracellular solution was Mg ²⁺ free ND 96 (NaCl 96 mM, KCl 2 mM, CaCl ₂ 1.8 mM, Hepes 5 mM, pH = 7.5), and the holding potential was 160 mV. NMDA currents were evoked by application of NMDA 100βΉί, glycine 10M. The recorded NMDA-induced inward current value was substituted into the following equation to calculate the% electrical response. % Electrical response = (value of NMDA-evoked inward current in the presence of test compound / value of NMDA-evoked inward current in the absence of test compound) XI 00 Normally, if the test compound exhibits NMDA receptor antagonism However, the inflow of Ca ions into nerve cells is reduced, and the electrical response% is reduced. Table 1 shows the% electrical response of the NR1 / NR2B complex receptor for each compound, and Table 2 shows the% electrical response for each complex receptor of NR1 / NR2AD.

(table 1 )

% Electrical response of NR1 / NR2B complex receptor

Compound No. Electric response%

4 1 6

5 2 1

7 8 2

8 8 3

(Table 2)

Electric response% by difference of NR 2 subfamily

Electric response%

Compound No. NR1 / NR2A NR1 / NR2B NR1 / NR2C NR1 / NR2D

4 9 4 1 6 1 0 9 9 0

5 9 3 2 1 1 0 4 8 7 In Table 1, compounds 7 and 8 with a benzene ring and a piperidine ring directly bonded 10877

In comparison, compounds 4 and 5 of the present invention, in which a methylene group was introduced between the benzene ring and the piperidine ring, had a lower% electrical response. Further, in Table 2, among the NR1 / NR2A to D complex receptors, only the NR1 / NR2B complex receptor had a decreased% electrical response. From the above results, it was clarified that Compounds 4 and 5, in which a methylene group was introduced between the benzene ring and the piperidine ring, had an antagonistic effect only on the NR1ZNR2B complex receptor. Test example 2

Receptor binding experiments

The aforementioned MK-801 is said to bind to PCP receptors and cause mental disorders. Thus, receptor competition experiments with MK-801 and the compounds of Examples 2 to 4 (Compounds 4 to 6) were performed.

Using male Slc: Wistar rats, the brain was excised after decapitation and the cerebral cortex was fractionated. The cerebral cortex was homogenized with 20 volumes of ice-cold 5 mM Tris · HC1 buffer (pH 7.8) and centrifuged at 4 ° C and 4000 OXg for 10 minutes. The obtained precipitate was suspended in the same buffer and centrifuged again. This operation was repeated twice, and the obtained precipitate was suspended in a buffer solution and stored at 180 ° C. Immediately before the experiment, after melting at room temperature, the mixture was centrifuged at 4 ° C. and 4000 OXg for 10 minutes, and the obtained precipitate was suspended in a buffer. It was further diluted 2.5-fold with a buffer solution and used as a membrane sample in the experiment.

In the binding experiment, the above membrane sample 480〃1, 10、1 [1] distilled water (total binding amount), [2] different concentration of test substance or [3] large amount of unlabeled ligand (non-specific Was added, and 101 more labeled ligands were added and incubated for a certain period of time. After incubation, the conjugate and the free body were separated using Whatman GP7C filter paper (manufactured by Whatman), and the filter paper was washed four times with 2.5 mL of ice-cold buffer. The filter paper was immersed in liquid scintillation (Clearsol I, manufactured by Nacalai Tesque, Inc.) in a vial, and the radioactivity was measured with a liquid scintillation counter. The binding inhibition rate was determined by the following equation, and the dose aC ₅₀ ) that inhibited binding by ₅₀ % was calculated. Incidentally, the last 2 for 60 min = 25 ° C in the ^[3 H] MK-801 co the Iotaiotamyu, the nonspecific binding using 10 〃M (+) MK-801. The IC ₅₀ values are shown in the table below. 10877

Haloperidol, a commercially available NR1 / NI12B complex receptor antagonist, was used as a control.

Binding inhibition rate (%) = 100-[([2]-[3]) / ([1]-[3]) X 100]

(Table 3)

IC ₅₀ value in PCP receptor binding experiment

Compound No. IC ₅₀ (M

4> 1 0 0

5> 1 0 0

6> 1 0 0

From Nono Roperi d'2 3 As a result, the PCP receptor, IC ₅₀ values in the case of applying the compound 4-6 is higher than that Haroperi doll, it became clear that they do not conflict with MK-801. Therefore, it is considered that the compound of the present invention does not cause side effects such as mental disorders. Test example 3

Effect on neuronal degeneration caused by Hypoxia (anoxic state, that is, cerebral infarction state) 2 mM NaCN, 2 mM 2-deoxy glucose was applied to rat cerebral cortex primary cultured neurons on day 9 of culture for 20 minutes, and Hypoxia was applied. . Immediately after termination of Hypoxia, 5, 10, 15 and 20 minutes later, the compounds of Examples 2 and 3 (compounds 4 and 5) [just after the compound concentration: 0.02 to 200 μΛΙί, and after 5 to 20 minutes: 20 ^ Μ] were applied. The effect of inhibiting neuronal degeneration 24 hours later was examined using MTT [3- (4,5-dimethyl-2-thiazolyl) -2 ₎ 5-diphenyltetrazolmm bromide] or LDH [Lactate dehydrogenase] activity as an index. MTT is an index of cell viability, and LDH is an index of cell death rate. As a result, in the application immediately after the termination of Hypoxia, Compound 4 showed a significant inhibitory effect on neuronal degeneration at 2 M or more and Compound 5 at 20 M or more, and Compound 4 showed a significant effect even when applied 5 minutes after the termination of Hypoxia. Suppressed neuronal degeneration. From the above results, it has been clarified that the compound of the present invention exhibits an inhibitory effect on neuronal degeneration even in an anoxic state such as cerebral infarction. Test example 4 Effects of NMDA on neuronal degeneration

After applying 50 M NMDA to primary cultured neurons of rat cerebral cortex on day 9 of culture for 10 minutes, the compounds of Examples 2 to 4 (compounds 4 to 6) [compound concentration of 0.02 to 200 jM] were applied. The effect of inhibiting neuronal degeneration 24 hours later was examined using MTT activity as an index. As a result, a significant inhibitory effect on neuronal degeneration was observed at 2 / M or more for compound 4, 20 化合物 M or more for compound 5, and 20 M or more for compound 6. Test example 5

Expression system experiments using HEK293T cells

When the NMDA receptor is expressed in HEK293T cells, large amounts of glutamate and aspartate are released from HEK293T cells, which can automatically induce cell degeneration. HEK293T cells were expressed at an NR1 / NR2B complex receptor complementary DNA (cDNA) ratio of 1: 3 (total amount of cDNA; 2 g / well (6-well plate)), and Example 2 for cell degeneration 24 hours later And 3 compounds (compounds 4 and 5) [The cytopathic inhibitory effect at a compound concentration of 2 M or 0.02-200 was examined using LDH activity as an index. As a result, in cells expressing the NR1ZNR2B complex receptor, Compounds 4 and 5 showed a significant cytopathic inhibitory effect at 20 M or more. Test example 6

Receptor binding experiments

[experimental method]

Using male Slc: Wistar rats, the brain was removed after decapitation and the cerebral cortex was fractionated. The preparation method and experimental method of the membrane sample differ depending on each receptor subtype, and are shown below.

Binding experiments were performed on a membrane sample of 480〃1, 10 ^ 1 [1] distilled water (total binding amount, Total), [2] different concentrations of test substance or [3] large amounts of unlabeled ligand (non- Specific binding amount (NS) and 10/1 labeled ligand were further added and incubated for a certain period of time. After the incubation, the conjugate and the free form were separated using Whatman GF / C filter paper, and the filter paper was washed four times with 2.5 ml of ice-cold buffer. Filter paper into liquid vial in vial The sample was immersed in a racion (Clearsol I) and the radioactivity was measured with a liquid scintillation counter. The binding inhibition rate was determined by the following formula, and the dose that inhibited binding by 50% (ICS _S ) was calculated.

Binding inhibition rate «) = 100-(([2]-[3]) I ([1]-[3]) X 100)

(1) [H] Ifenprodil

Homogenize the cerebral cortex with 20 volumes of ice-cold 50 mM Tris-HCl buffer (pH 7.4),

Centrifuged at 40,000 × g for 10 minutes. The obtained precipitate was suspended in the same buffer and centrifuged again. This operation was repeated twice, and the resulting precipitate was suspended in the same buffer and stored at -80 ° C. On the day of the experiment, after melting at room temperature, the mixture was centrifuged at 4 ° C and 40,000 Xg for 10 minutes, and the obtained precipitate was suspended in the same buffer and further diluted 10-fold. NR1 + NR2B-expressing cells (HEK293T) are buffered with 20 mM HEPES (: N-2-hydroxyhexylpiperazine-Ν'-2-ethanesulfonic acid) buffer, ImMEDTA (: ethylenediaminetartaric acid-2-sodium salt) buffer (PH 7.0), centrifuged at 4 ° C, 100, OOOXg for 30 minutes, and used for experiments after resuspension. Incubation was carried out at 4 ° C for 2 hours with a final 5 nM (15 nM cells) [ ³ H] Ifenprodil. For nonspecific binding, 100 IfM Ifenprodil. Tartrate was used, and the filter paper was pretreated with 0.05% polyethyleneimine. The incubation was performed with 3 3M vanoxerine to block the binding of [] ifenprodil to the sigma receptor.

(Table 4) IC50 (u)

Formulation Example 1

An appropriate amount of the compound 4, the crystalline cellulose, the magnesium stearate and the like of Example 2 is mixed, and the mixture is compressed to give a tablet.

Formulation Example 2

An appropriate amount of the compound 4 of Example 2, lactose, magnesium stearate and the like are mixed and granulated to obtain granules.

Formulation Example 3 Capsules are obtained by filling the granules of Formulation Example 2 into capsules. Industrial applicability

The present compound is useful as a drug for treating acute phase of cerebral infarction or a drug for treating chronic neurodegenerative disease.

Claims

The scope of the claims

1. Formula (I)

(Where

Α is —NR ¹ — (CH ₂ ) m- (R ¹ is hydrogen or lower alkyl; m is an integer of 2 to 5) or a single bond;

Z ¹ and Z ² are each independently a substituent selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, lower alkenyl, halogen, lower alkyl halide, lower alkoxy halide, hydroxy, carboxy and nitro. A group; n represents an integer of 1 to 3; )

2. The compound according to claim 1, wherein A is —NR ¹ — (CH ₂ ) m— (wherein each symbol is as defined above), a pharmaceutically acceptable salt thereof, a prodrug thereof, or a salt thereof. Solvate.

3. The compound according to claim 1, wherein A is a single bond, a pharmaceutically acceptable salt thereof, a prodrug thereof or a solvate thereof.

4. Z ¹ is hydrogen, and Z ² is a substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkenyl, halogen, lower alkyl halide, lower alkoxy halide, hydroxy, carboxy, and nitro The compound according to claim 1, a pharmaceutically acceptable salt thereof, a prodrug thereof or a solvate thereof.

5. The method of claim ¹ , wherein Z ¹ is hydrogen and Z ² is a tt substituent selected from the group consisting of methyl, butyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy and hydroxy. The compound according to 4, a pharmaceutically acceptable salt thereof, The prodrugs or their solvates.

6. A is — NR ¹ — (CH ₂ ) m- (where R ¹ is hydrogen or lower alkyl; m is 2 or 3); n is 1; Z ¹ is hydrogen; Z ² is lower alkyl, lower alkoxy The compound according to claim 1, which is a substituent selected from the group consisting of: lower alkenyl, halogen, lower alkyl halide, lower alkoxy halide, hydroxy, carboxy and nitro. Drag or their solvates.

7. A is a single bond; n is 1; Z ¹ is hydrogen; Z ² is from the group consisting of lower alkyl, lower alkoxy, lower alkenyl, halogen, halogenated lower alkyl, halogenated lower alkoxy, hydroxy, carboxy and nitro 2. The compound according to claim 1, which is a substituent selected, a pharmaceutically acceptable salt thereof, a prodrug thereof or a solvate thereof.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, a mouth drag thereof, or a solvate thereof.

9. The pharmaceutical composition according to claim 8, which is an NMD A receptor antagonist.

10. The pharmaceutical composition according to claim 9, which is an antagonist of a complex receptor of NR1 and NR2B, which are subunits of the NMD A receptor.

1 1. The pharmaceutical composition according to claim 8, for suppressing neuronal degeneration due to NMDA and / or hypoxia.

12. The pharmaceutical composition according to claim 8, which is a therapeutic agent for acute phase of cerebral infarction or a therapeutic agent for chronic neurodegenerative disease. '

1 3. The pharmaceutical composition according to claim 8, which is an analgesic.

14. Prevention of a disease caused by an NMD A receptor characterized by administering a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, a prodrug thereof or a solvate thereof. Or treatment method.

15. The compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, a prodrug thereof or a method thereof for producing a prophylactic or therapeutic agent for a disease caused by an NMD A receptor. Use of a solvate of