JP4590260B2 - 1,3,5-triazine derivatives as ligands to the human adenosine-A3 receptor - Google Patents

Description

The present invention relates to a group of novel triazine derivatives which are ligands for human adenosine -A ₃ receptors. The invention also relates to pharmaceutical compositions comprising as active ingredient at least one pharmacologically active amount of these novel triazine derivatives.

Caffeine and theophylline are two well-known natural compounds that exert their pharmacological activity by interacting with adenosine receptors. This discovery had a major impact on adenosine receptor research. Currently, four types of adenosine receptors have been identified and called A ₁ , A _2A , A _2B and A ₃ respectively. All four types belong to the superfamily of 7-transmembrane G-protein coupled receptors. Adenosine receptors are ubiquitous and are involved in many different biological processes. Thus, over the past decades, the therapeutic potential of adenosine receptor ligands has generated numerous research interests. Recent reviews are Non-Patent Document 1 and Non-Patent Document 2.

Ligands to various adenosine receptors are the subject of numerous patent applications and patents. Only two of those triazines are described. Patent Document 1 describes a series of 2,4-bisphenyl substituted triazines showing nanomolar affinity for human adenosine -A ₁ receptor.

Patent Document 2, which is a second patent describing triazine, is the closest prior art. It describes a series of substituted 1,3,5-triazine which is a ligand for human adenosine -A ₃ receptors, their strongest ones having an affinity of approximately 15 nM.
WO991163 Japanese Patent Laid-Open No. 11-158073 S. Hess, Regent advancements inadenosine receptor antagonist research, Expert Opin. Ther. Patents, 11, 1547-1562, 2001. M.M. A. Jacobson, Adenosine receptor agonists, Expert Opin. Ther. Patents 12 (4), 489-501, 2002.

Surprisingly, found in a series of triazine derivatives with novel combinations of substituents, a group of compounds, to indicate that it has an affinity for human adenosine -A ₃ receptors wherein the low nanomolar range did.

  The present invention relates to a general formula (1)

[Where,
R ₁ is halogen, alkyl (1-3C), O-alkyl (1-3C), CF ₃ , NH ₂ , N- (di) -alkyl (1-3C), N- (di) -alkenyl (1 -3C), N- (di) -alkynyl (1-3C), N-alkyl (1-3C) alkenyl (1-3C), N-alkyl (1-3C) alkynyl (1-3C), N-alkenyl _C 2 -C ₈ substituted by (l-3C) alkynyl (l-3C) or - a cycloalkyl group,
R ₂ , R ₃ and R ₄ are independently H, halogen, alkyl (1-3C), CF ₃ , OH, O-alkyl (1-3C),
Phenoxy, hydroxyalkyl (1-3C), alkoxy (1-2C) -alkyl (1-2C), phenyl, N- (di) -alkyl (1-3C),
1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF ₃ , SCH ₃ , SOCH ₃ , SO ₂ CH ₃ or R ₂ and R ₃ together with the phenyl ring to which they are attached, optionally Represents a substituted benzofuran, dihydrobenzofuran, benzodioxane, benzodioxolane or naphthalene ring system;
X is, NH, N-alkyl _{(1-3C), CH 2, O} , S or carbon - represents a carbon bond,
Y represents the general formula (A), (B) or (C):

[Where,
R ₅ is either OH or CH ₂ OH;
R ₆ represents H, alkyl (1-3C), phenyl, NH ₂ , N- (di) -alkyl (1-3C), OH, O-alkyl (1-3C) or hydroxyalkyl (1-2C). Represent,
n has a value of 0, 1 or 2;
R ₇ represents alkyl (1-3C), benzyl, hydroxyalkyl (1-2C) or methoxyalkyl (1-2C);
R ₈ and R ₉ are independently H, halogen, alkyl (1-3C), CF ₃ , OH, O-alkyl (1-3C), N- (di) -alkyl (1-3C), 1- Represents morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF ₃ , SCH ₃ , SOCH ₃ , or SO ₂ CH ₃ ;
R ₁₀ represents H or alkyl (1-3C);
R ₁₁ represents H, alkyl (1-3C), benzyl, hydroxyalkyl (1-2C) or methoxyalkyl (1-2C);
Z represents a group of NOH, NO alkyl (1-3C), O or S].
And pharmacologically acceptable salts thereof.

  In the description of substituents, the abbreviation “alkyl (1-3C)” means “methyl, ethyl, n-propyl or isopropyl”.

As used herein, “C ₂ -C ₈ cycloalkylamino” means any cyclic amine containing 2-8 carbons in the ring. The cycloalkylamino ring may contain other atoms and may be optionally substituted. Examples of C ₂ -C ₈ cycloalkylamino include pyrrolidinyl, piperidinyl, morpholinyl, aziridinyl, pyrrolinyl and the like.

As used herein, “optionally substituted” means that the group is alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxyl, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, It may be further substituted with one or more groups selected from dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, oxo, nitro, acyl, amide, alkylamide, dialkylamide, carboxyl Or 2 optional substituents containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur together with the carbon atom to which they are attached. It means that a 6-membered aromatic or non-aromatic ring may be formed. To. Any substituent may itself have additional optional substituents. Preferred optional substituents include C _1-3 alkyl, such as methyl, ethyl, and trifluoromethyl, fluoro, chloro, bromo, hydroxyl, C _1-3 alkyloxy, such as methoxy, ethoxy, and trifluoromethoxy, and amino Is included.

  All compounds having the formula (1) in which the substituent on the asymmetric carbon atom is either R-configuration or S-configuration belong to the present invention.

  Prodrugs, that is, compounds that are metabolized to a compound having formula (1) when administered to humans by any known route also belong to the present invention. In particular, this relates to compounds having primary and secondary amino groups or hydroxyl groups, ie those in which typical examples are compounds having the formula (9) and their enantiomers (see below). Such compounds can react with organic acids to produce compounds that can be metabolized to compounds having formula (1).

The present invention is particularly, _{R 1} is halogen, alkyl (l-3C), O-alkyl _{(1-3C), CF 3, NH} 2 or N- (di) - formula (1 representing an alkyl (l-3C) ) And other symbols have the meanings given above.

More particularly, the present invention relates to R ₁ = Cl,
R ₂ = H, X = NH, Y is any of the groups (A), (B) or (C), R ₆ = H, n = 1, Z = O, R ₁₀ = H, and R ₃ , R ₄ , R ₅ , R ₇ , R ₈ , R ₉ and R ₁₁ relate to compounds having the formula (1) as defined above, and all possible stereoisomers as outlined above And prodrugs and are thus represented by general formulas (2), (3) and (4).

More specifically, the present invention relates to R ₅ = 3-CH ₂ OH, R ₇ = CH ₃ , R ₈ = H, R ₉ = H, R ₁₁ = CH ₃ and R ₃ and R ₄ are as defined above Including all possible stereoisomers and prodrugs described above in relation to any compound of formula (2), (3) or (4) having the general formula (5), ( 6) and (7).

  More preferred are compounds having formula (8) and their enantiomers.

  The best mode of the invention is a compound represented by formula (9).

This compound _has an affinity for human adenosine -A ₃ receptors pK i 9.0 ± 0.3.

The compounds of the invention and their salts can be obtained according to the general scheme outlined below. Those with R ₁ = Cl are synthesized according to Scheme 1.

The experimental details of the first step in this general scheme are: Amer. Chem. Soc. 116, 1994, 4326,
For X = N-alkyl, see Chem. Pharm. Bull. 45, 1997, 291,
For _{· X = CH 2, Tetrahedron 56,2000,9705} ,
・ For X = O, Pol. J. et al. Chem. 74, 2000, 837,
・ For X = S, J. Chem. Soc. C 1967,466, and Tetrahedron 56, 2000, 9705 for X = carbon-carbon bond
It is described in.

The compounds of the invention having R ₁ = F or Br can be obtained in exactly the same way from the corresponding tri-halo derivatives. The experimental details are as follows: • For the case where R ₁ is F; Med. Chem. 36 (26), 4195-4200, 1993, and R ₁ = Br. Prakt. Chem. 82, 536, 1910,
It is described in.

R ₁ ═O-alkyl (1-3C) or amine substituent: NH ₂ , N- (di) -alkyl (1-3C), N- (di) -alkenyl (1-3C), N- (di) -Alkynyl (1-3C), N-alkyl (1-3C) alkenyl (1-3C), N-alkyl (1-3C) alkynyl (1-3C), N-alkenyl (1-3C) alkynyl (1- Compounds of the invention having either 3C) or optionally substituted C ₂ -C ₈ cycloalkylamino groups can be obtained by further substitution of chloro derivatives as outlined in Scheme 2 below.

Experimental details include: • Heterocycles 31 (5), 895-909, 1990 for R ₁ = alkoxy, and Tetrahedron, 54 (1998) 4051-4056, for R ₁ = (substituted) amine.
It is described in.

Compounds of the invention having R ₁ = alkyl (1-3C), CF ₃ or iodine can be obtained according to the order of the synthetic steps outlined in Scheme 3 below.

Experimental details are as follows: • For R ₁ = alkyl Med. Chem. 42 (5), 805-818, 1999,
• For R ₁ = CF ₃ Chem. Soc. , Chem. Comm 1988, (10) 638-639, and • R ₁ = Iodine, Eur. J. et al. Org. Chem. , 2002, 4181-4184,
It is described in.

  Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, such as mixing the compounds of the present invention with a compatible acid.

  Suitable acid addition salts are inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid, or organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, It can be formed using p-toluenesulfonic acid, methanesulfonic acid and naphthalenesulfonic acid.

The compounds of the invention of general formula (1), as well as their salts, have adenosine-A ₃ (anti) agonist activity. They adenosine -A ₃ receptor are useful in the treatment of those that can be treated via manipulation of disorders involving or their receptors. Inflammatory diseases including acute and chronic pain, arthritis, multiple sclerosis, asthma and psoriasis; gastrointestinal diseases such as ulcers, inflammatory bowel disease (Crohn's disease) and ulcerative colitis; allergic reactions such as Eczema, atopic dermatitis and rhinitis; cardiovascular disorders such as myocardial infarction, arrhythmia, hypertension, thrombosis, anemia, arteriosclerosis, angina, skin diseases such as urticaria, lupus erythematosus and itching; ophthalmology such as glaucoma Diseases; Chronic obstructive pulmonary disease, respiratory disorders including bronchitis and pancreatic cystic fibrosis; various forms of epilepsy, stroke, depression, central nervous system disorders including sleep apnea; cognitive and memory dysfunction Disorders characterized by, for example, Alzheimer's disease, Creutzfeldt-Jakob disease, Huntington's disease, Parkinson's disease, neurorehabilitation (posttraumatic brain injury); acute Or spinal cord injury; diabetes, useful osteoporosis, immune system diseases, various cancers and leukosis, in bacterial and viral infections.

Adenosine -A ₃ receptor (anti) agonists of the compounds of the present invention were determined using the methods described Compendium below.
Affinity receptor binding Human Adenosine -A ₃ the compound to the receptor to the human adenosine -A ₃ receptors, C. A. Salvator et al., "Molecular Cloning and characterization of the human _{A 3} adenosine receptor" (C.A.Salvatore et al.:Molecular cloning and characterization of the human A 3 adenosine receptor, Proc.Natl.Acad.Sci.USA, 90, 10365-10369, 1993). In summary, membrane preparations were obtained from human recombinant (HEK293) cells Human adenosine -A ₃ receptors are stably expressed. Membranes were incubated for 90 minutes at 22 ° C. with [ ¹²⁵ I] -AB-MECA in the absence or presence of test compounds in the concentration range from 10 μM to 0.1 nM diluted in appropriate buffer. Separation of bound radioactivity from free radioactivity was performed by filtration through a Packard GF / B glass fiber filter washed several times with ice-cold buffer using a Packard cell harvester. Bound radioactivity was measured using a scintillation counter (Topcount, Packard) using a liquid scintillation cocktail (Microscint 0, Packard). The measured radioactivity is plotted against the concentration of the displacement test compound and the displacement curve is calculated by a four parameter logistic regression method to obtain an IC ₅₀ curve, ie the concentration of the displacement compound at which 50% of the radioligand is displaced. It was. The affinity pK ₁ value is the Cheng-Prusoff equation pK ₁ = −log (IC ₅₀ / (1 + S / K _d ))
In which IC ₅₀ is described above, S is the [ ¹²⁵ I] -AB-MECA concentration (typically 0.1 nM) used in the assay expressed in mol / l, and K _d is human is the equilibrium dissociation constant of ^[125 I] -AB-MECA for adenosine -A ₃ receptors (0.22 nM)] correcting an _{IC 50} curve for radioligand concentration and its affinity for the human adenosine -A ₃ receptors according to Calculated.

The compounds of the present invention have a high affinity for adenosine -A ₃ receptors in the binding assay described above. This property is useful in the treatment of disorders adenosine -A ₃ receptor can be treated via manipulation of disorders involving or their receptors.

(1S, 2R) -2-{[4-Chloro-6- (3,4-methylenedioxy-phenylamino)-[1,3,5] triazin-2-yl] -amino} -1-phenyl- To a solution of cyanuric acid chloride (1.84 g) in acetonitrile (20 ml) maintained at a temperature of −20 ° C. with stirring with propan-1-ol was added 3,4-methylenedioxy- in acetonitrile (20 ml). A solution of aniline (1.37 g) and diisopropylethylamine (DIPEA) (1.29 g) in acetonitrile (20 ml) was added dropwise in sequence. After stirring at −20 ° C. for 1 hour, a solution of DIPEA (1.29 g) in acetonitrile (20 ml) and (1S, 2R)-(+)-norephedrine (1.51 g) in acetonitrile (20 ml) was in turn. Added dropwise. The mixture was warmed to room temperature and stirred for an additional 2 hours. The resulting reaction mixture was concentrated under reduced pressure. After adding ethyl acetate (250 ml), the organic layer was washed sequentially with HCl solution in water (1M, 100 ml), NaOH solution in water (1M, 100 ml) and brine (50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by column chromatography using silica gel and a mixture of heptane: ethyl acetate (3: 1) as eluent. The resulting pure product (Formula (9), see above, Example B-44, see table) was obtained as a white solid, 80% yield.

  The present invention is further illustrated using the following specific examples shown in the table below and is represented by the general formula

[Wherein Y represents a group of the general formula (A), (B) or (C)]

It is represented by

  These examples are only intended to illustrate the invention in more detail and are therefore not considered to limit the scope of the invention in any way.

Prodrug Example To illustrate the concept of “prodrug”, the following compound having the general formula (10) was prepared.

Prodrugs having formula (10), has no affinity for human adenosine -A ₃ receptors, but after hydrolysis they generate the compound with highly active of formula (9) (see above).

Claims (6)

Formula (1)

[Where,
R ₁ represents a chlorine atom, methyl, methoxy, NH ₂ , N-dimethyl, 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl, NH-propargyl or N (CH ₃ ) propargyl group;
R ₂ , R ₃ and R ₄ independently represent H, Cl, F, methyl, CF ₃ , methoxy, ethoxy, phenoxy, hydroxyalkyl (1-2C), 1-morpholinyl, or R ₂ and R ₃ are Together with the phenyl ring to which they are attached represents a methylenedioxyphenyl or naphthalene ring,
X is NH, N-methyl, CH _2, O, S or carbon - represents a carbon bond,
R ₇ represents alkyl (1-3C), benzyl or hydroxymethyl;
R ₈ and R ₉ independently represent H, OH or methoxy;
R ₁₀ represents H or methyl]
Or a pharmacologically acceptable salt thereof, or all compounds having the formula (1) wherein the substituent on the asymmetric carbon atom, if present, is in either the R-configuration or the S-configuration. Claims wherein R ₁ = Cl, R ₂ = H, X = NH, R ₁₀ = H and R ₃ , R ₄ , R ₇ , R ₈ and R ₉ have the formula (1) with the same meaning as in claim 1 Item 1. The compound according to Item 1. R ₁ = Cl, R ₂ = H, X = NH, R ₇ = CH ₃ , R ₈ = H, R ₉ = H, R ₁₀ = H, and R ₃ and R ₄ have the same meaning as in claim 1 The compound of claim 1 having the formula (1) Formula (8)

The compound of Claim 1 shown by these, or its enantiomer. Formula (9)

The compound of Claim 1 shown by these. Formula (10)

[Where:
R is selected from propionyl, pivaloyl, nicotinoyl, N-acetyl-isonipecotyl, methoxyacetyl, acetoxyacetyl and nonaoil]
A compound represented by