KR100823799B1 - Benzothiazole derivatives - Google Patents

Abstract

The present invention relates to compounds of formula (IA) or (IB), and pharmaceutically acceptable acid addition salts thereof:

Formula IA

Formula IB

Where

R ¹ , R ² are independently of each other lower alkyl or — (CH ₂ ) _m —O-lower alkyl, or together with the N atom to which they are attached form a heterocyclic ring;

R ³ is hydrogen or lower alkyl;

R ⁴ is lower alkyl;

hetaryl is 3H-imidazole-2,4-diyl or 1H-pyrazole-1,4-diyl;

n is 1 or 2;

m is 1 or 2.

The compound may be used in the treatment of drug addictions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, neuroprotection, schizophrenia, anxiety, pain, respiratory deficiency, depression, ADHD, amphetamines, cocaine, opioids, ethanol, nicotine, cannabinoids, or asthma , Allergic reactions, hypoxia, ischemia, seizures and substance abuse, or as a sedative, muscle relaxant, antipsychotic, antiepileptic, anticonvulsant, and coronary artery disease and heart failure.

Description

Benzothiazole derivatives {BENZOTHIAZOLE DERIVATIVES}

The present invention relates to compounds of formula (IA) or (IB), and pharmaceutically acceptable acid addition salts thereof:

Where

R ¹ , R ² are independently of each other lower alkyl or — (CH ₂ ) _m —O-lower alkyl, or together with the N atom to which they are attached form a heterocyclic ring;

R ³ is hydrogen or lower alkyl;

R ⁴ is lower alkyl;

hetaryl is 3H-imidazole-2,4-diyl or 1H-pyrazole-1,4-diyl;

n is 1 or 2;

m is 1 or 2.

Surprisingly, compounds of formula (IA) or (IB) have been found to be adenosine A _2A receptor ligands. In particular, the compounds of the present invention have good affinity for A _2A -receptors and high selectivity for A ₁ -and A ₃ receptors.

Adenosine regulates a wide range of physiological functions by interacting with specific cell surface receptors. The possibility of adenosine receptors as drug targets was first considered in 1982. Adenosine includes bioactive nucleotides adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and cyclic adenosine monophosphate (cAMP); Structurally and metabolically related to the biochemical methylating agent S-adenosyl-L-methionine (SAM); Coenzyme NAD, FAD and coenzyme A; And structurally related to RNA. Adenosine and related compounds together are important for the regulation of various aspects of cellular metabolism and for the regulation of various central nervous system activities.

Adenosine receptors have been classified into A ₁ , A _2A , A _2B and A ₃ receptors belonging to the G protein-coupled receptor class. Activation of adenosine receptors by adenosine initiates a signal transduction mechanism. The mechanism is dependent on receptor bound G protein. Adenosine receptor subtypes each feature adenylate cyclase effector systems that traditionally use cAMP as the second messenger. A ₁ and A ₃ receptors coupled with G _i proteins inhibit adenylate cyclase to reduce cellular cAMP levels, while A _2A and A _2B receptors are coupled to G _S proteins and between adenylate Activate the clase to increase cellular cAMP levels. The A ₁ receptor system is known to activate phospholipase C and regulate both potassium and calcium ion channels. In addition to binding to adenylate cyclase, the A ₃ subtype also stimulates phospholipase C and activates calcium ion channels.

A ₁ receptors (326-328 amino acids) have been cloned from various species (dog, human, rat, cane, chick, bovine, guinea-pig) with 90-95% sequence identity between mammalian species. A _2A receptors (409-412 amino acids) were cloned from dogs, rats, humans, guinea pigs and mice. A _2B receptor (332 amino acids) was cloned from humans and mice having 45% homology with human A ₁ and A _2A receptors and human A _2B . A ₃ receptors (317-320 amino acids) were cloned from humans, rats, dogs, rabbits and sheep.

A ₁ and A _2A receptor subtypes have been shown to play a complementary role in the adenosine regulation of energy supply. Adenosine, a metabolite of ATP, diffuses from the cell and acts locally to activate the adenosine receptors, thereby reducing oxygen demand (A ₁ ) or increasing oxygen supply (A _2A ), thus balancing energy supply: To recover. The action of both subtypes is to increase the amount of oxygen available to the tissue and protect the cells against damage caused by short-term imbalances of oxygen. One of the important functions of endogenous adenosine is to prevent injury during trauma such as hypoxia, ischemia, hypotension and seizures.

It is also known that binding of adenosine receptor agonists to mast cells expressing rat A ₃ receptor results in increased inositol triphosphate and intracellular calcium concentrations, which has enabled antigen-induced secretion of inflammatory mediators. have. Therefore, A ₃ receptors play a role in mediating asthma attacks and other allergic reactions.

Adenosine is a neurotransmitter that can regulate many aspects of physiological brain function. Endogenous adenosine, the central link between energy metabolism and neuronal activity, depends on behavioral patterns and (pathological) physiological conditions. Under conditions of increased damage and reduced energy availability (eg, hypoxia, hypoglycemia and / or excessive neuronal activity) adenosine provides a strong protective feedback mechanism. Interactions with adenosine receptors represent promising targets for therapeutic treatment in many neurological and psychotic disorders such as epilepsy, paralysis, motor disorders (Parkinson's or Huntington's disease), Alzheimer's disease, depression, schizophrenia or addiction. Increases in neurotransmitter release appear after trauma such as hypoxia, ischemia and seizures. These neurotransmitters ultimately cause neuronal degeneration and neuronal death that cause individual brain damage or brain death. Therefore, adenosine A ₁ agonists that mimic the central inhibitory effects of adenosine may be useful as neuroprotective agents. Adenosine has been proposed as an endogenous anticonvulsant that inhibits glutamate release from excitatory neurons and inhibits nerve stimulation. Therefore, adenosine agonists can be used as therapeutic agents for epilepsy. Adenosine antagonists have been shown to stimulate the activity of the CNS and to be effective as cognitive enhancers. Selective A _2A antagonists have therapeutic potential in the treatment of various forms of dementia such as Alzheimer's disease, and neurodegenerative diseases such as stroke. Adenosine A _2A receptor antagonists regulate the activity of progenitor GABA neurons and modulate flexible and properly cooperative movement, providing potential treatment for Parkinson's disease symptoms. Adenosine is also involved in many physiological processes involving sedation, hypnosis, schizophrenia, anxiety, pain, respiration, depression and drug addiction (amphetamines, cocaine, opioids, ethanol, nicotine, cannabinoids). Therefore, drugs acting on adenosine receptors have therapeutic potential as sedatives, muscle relaxants, antipsychotics, anti-anxiety agents, analgesics, respiratory stimulants, antidepressants and for drug abuse. They can also be used to treat ADHD (Attention Deficit Hyperactivity Disorder).

An important role of adenosine in the cardiovascular system is as a cardioprotectant. The level of endogenous adenosine is increased for ischemia and hypoxia and protects cardiac tissue during and after trauma (pretreatment). Adenosine A ₁ agonists can act on the A ₁ receptor to protect against damage caused by myocardial ischemia and reperfusion. The regulatory effect of the A _2A receptor on adrenergic function can be related to various diseases such as coronary artery disease and heart failure. A _2A antagonists may have therapeutic advantages in situations where an enhanced anti-adrenergic response is desired, such as in acute myocardial ischemia. Selective antagonists at the A _2A receptor can also augment the effect of adenosine in terminating ventricular arrhythmias.

Adenosine regulates many aspects of renal function, including renin release, glomerular filtration rate, and renal blood flow. Compounds that antagonize the action of adenosine have the potential as kidney protectors. In addition, adenosine A ₃ and / or A _2B antagonists may be useful for the treatment of asthma and other allergic reactions and / or for the treatment of diabetes and obesity.

Many documents, such as the following, describe current knowledge about adenosine receptors: Bioorganic & Medicinal Chemistry , 6 , 619-641, 1998; Bioorganic & Medicinal Chemistry , 6 , 707-719, 1998; J. Med. Chem ., 41 , 2835-2845, 1998; J. Med. Chem ., 41 , 3186-3201, 1998; J. Med. Chem ., 41 , 2126-2133, 1998; J. Med. Chem ., 42 , 706-721, 1999; J. Med. Chem ., 39 , 1164-1171, 1996; Arch. Pharm. Med. Chem ., 332 , 39-41, 1999; Am. J. Physiol ., 276 , H1113-1116, 1999; or Naunyn Schmied, Arch. Pharmacol ., 362 , 375-381, 2000].

The object of the present invention is the use of a compound of formula IA or IB and a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a disease associated with adenosine A _2A receptor itself, a compound of formula IA or IB, a process for the preparation thereof, the present invention. In addition to the medicaments based on the compounds according to the invention and their preparation, the use of the compounds of formula (IA) or (IB) in the inhibition or prevention of diseases based on the regulation of adenosine systems such as: Alzheimer's disease, Parkinson's disease, Huntington's disease Neurotoxicity, schizophrenia, anxiety, pain, respiratory deficiency, depression, amphetamines, cocaine, opioids, drug addictions such as ethanol, nicotine, cannabinoids, or asthma, allergic reactions, hypoxia, ischemia, seizures and substance abuse. In addition, the compounds of the present invention may be useful as cardioprotectants for diseases such as sedatives, muscle relaxants, antipsychotics, antiepileptics, anticonvulsants and coronary artery disease and heart failure. The most preferred indications according to the invention are based on A _2A receptor antagonist activity and treatment of conditions including central nervous system diseases such as Alzheimer's disease, certain depressive disorders, drug addiction, neuroprotection and Parkinson's disease as well as treatment of ADHD. Or prevention.

As used herein, the term "lower alkyl" refers to saturated straight or branched chain alkyl groups containing 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2 -Butyl, t-butyl and the like. Preferred lower alkyl groups are groups having from 1 to 4 carbon atoms.

The term "heterocyclic ring" means a saturated carbon ring system which may have a heteroatom, preferably O or N-atom, in addition to the N atom. Examples of such rings are morpholine or pyrrolidine.

The term "pharmaceutically acceptable acid addition salts" refers to inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, salts with p-toluenesulfonic acid and the like.

Preferred compounds of the present application are compounds of formula (IA). More particularly, compounds wherein hetaryl is 3H-imidazole-2,4-diyl are preferred, for example the following compounds:

2-([(2-Methoxy-ethyl) -methyl-amino] -methyl) -3-methyl-3H-imidazole-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothia Zol-2-yl) -amide,

2-dimethylaminomethyl-3-methyl-3H-imidazol-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide,

3-Methyl-2-morpholin-4-ylmethyl-3H-imidazole-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide, or

3-Methyl-2-pyrrolidin-1-ylmethyl-3H-imidazol-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide.

Preference is also given to compounds of the formula (IA) in which the hetaryl is 1H-pyrazole-1,4-diyl, for example,

1- (2-Pyrrolidin-1-yl-ethyl) -1H-pyrazole-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide,

1- (2-Dimethylamino-ethyl) -1 H-pyrazole-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide, or

1- (2-Morpholin-4-yl-ethyl) -1 H-pyrazole-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide.

Preferred compounds of the present application are also compounds of formula (IB). More particularly, compounds wherein hetaryl is 3H-imidazole-2,4-diyl are preferred, for example, the following compound: 2-methoxymethyl-3-methyl-3H-imidazole-4-carboxylic acid (4- Methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide.

Also preferred are compounds of formula IB wherein hetaryl is 1H-pyrazole-1,4-diyl, for example, the following compound: 1- (2-methoxy-ethyl) -1H-pyrazole-4-carboxylic acid ( 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide.

Compounds of formula (IA) or (IB) of the present invention and pharmaceutically acceptable salts thereof may be prepared by methods known in the art, for example by the methods described below, including:

(a) reacting a compound of formula II with a compound of formula III to yield a compound of formula IA; or

(a ') reacting a compound of formula II with a compound of formula IV to give a compound of formula IB

If desired, the obtained compound is converted to a pharmaceutically acceptable acid addition salt:

Formula IA

Formula IB

In the above, R ¹ , R ² , R ³ , hetaryl and n have the meanings indicated above.

In Examples 1-9, the preparation of the compounds of formulas IA and IB is described in more detail.

Starting materials are known compounds or can be prepared according to methods known in the art.

Preparation of Compounds IA and IB

Intermediate 7- (morpholin-4-yl) -4-methoxy-benzothiazol-2-ylamine can be prepared according to the method disclosed in WO 01/97786. The preparation of compounds of formulas IA and IB using intermediates of formula II is generally described in WO 01/97786.

Compound of Formula IA :

To a solution of 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine (II) in tetrahydrofuran at about −70 ° C., add a solution of tert butyllithium in pentane and give a suspension Warm to about -30 ° C. At this time, a solution of the corresponding heteroaryl-carboxylic acid phenyl ester (similar to formula III) in tetrahydrofuran is added and the mixture is stirred at room temperature for about 1 hour. The reaction mixture is treated with saturated ammonium chloride solution followed by ethyl acetate and the resulting precipitate is collected, dried and purified by conventional methods.

Compound of formula IB :

Compounds of formula (IB) are prepared as described above using 4-methoxy-7-morpholin-4-yl-benzothiazol-3-ylamine (II) and heteroaryl-carboxylic acid phenyl esters (similar to formula IV) It can be prepared similarly to.

Isolation and Purification of Compounds

Isolation and purification of the compounds and intermediates described herein may optionally include any suitable separation or purification procedures, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, preparative low pressure or High pressure liquid chromatography or a combination of these procedures. Specific examples of suitable separation and isolation procedures can be obtained by reference to the following Preparations and Examples herein. However, other equivalent separation or isolation procedures can of course also be used.

Salts of Compounds of Formula IA or IB

The compound of formula (IA) or (IB) may be basic, for example, if the residue R contains a basic group such as an aliphatic or aromatic amine residue. In this case, the compound of formula I can be converted to the corresponding acid addition salt.

The conversion can be carried out at least in stoichiometric amounts of suitable acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, mal It is carried out by treating with lonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like and acid is added to a similar solvent. The temperature is maintained at 0 to 50 ° C. The resulting salt may spontaneously precipitate or precipitate out of solution with a less polar solvent.

Acid addition salts of the basic compounds of formula (IA) or (IB) can be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium hydroxide or potassium, potassium carbonate, sodium bicarbonate, ammonia, and the like. .

Compounds of formula (IA) or (IB) and their pharmaceutically useful addition salts have various pharmacological properties. In particular, the compounds of the present invention have been found to be adenosine receptor ligands and have high affinity for adenosine A _2A receptors.

The compounds were investigated according to the test shown below.

Human adenosine A _2A  Receptor

The human adenosine A _2A receptor was recombinantly expressed in Chinese hamster ovary (CHO) cells using a semliki forest virus expression system. Cells were harvested, washed twice by centrifugation, homogenized and washed again by centrifugation. The final washed membrane pellets were suspended in Tris (50 mM) buffer (Buffer A) containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl ₂ and 10 mM MgCl ₂ (pH 7.4). [ ³ H] -SCH-58261 [Dionisotti et al., Br. J. Pharmacol ., 121 , 353, 1997] (1 nM) binding assays showed that about 2.5 μg of membrane protein, 0.5 mg of Ysi-poly-l-lysine SPA beads and 0.1 U of adenosine in a final volume of 200 μl of Buffer A Performed in 96-well plates in the presence of diminase. Non-specific binding was defined using xanthine amine homologue (XAC; 2 μM). Compounds were tested at 10 concentrations from 10 μM to 0.3 nM. All analyzes were performed in duplicate and repeated two more times. Assay plates were incubated at room temperature for 1 hour before centrifugation and the bound ligands were then measured using a Packard Topcount scintillation counter. IC ₅₀ values were calculated using a non-linear curve fitting program and Ki values were calculated using the Cheng-Prussoff equation.

The pKi values of the compounds of the present application range from 8.8 to 9.4. Preferred compounds exhibit a pKi greater than 9.0.

Compounds of formula IA or IB and pharmaceutically acceptable salts of compounds of formula IA or IB can be used, for example, as medicaments in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, administration can also be carried out parenterally, for example, in the form of suppositories, or in the form of injections.

The compounds of formula (IA) or (IB) can be processed using pharmaceutically inert, inorganic or organic carriers for the preparation of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as carriers for tablets, coated tablets, sugar tablets and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols and the like. However, depending on the nature of the active substance no carrier is required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for controlling osmotic pressure, buffers, masking agents or antioxidants. They may also contain another therapeutically useful substance.

Pharmaceuticals containing a compound of formula (IA) or (IB) or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also objects of the present invention and include one or more compounds of formula (IA) or (IB) and / or pharmaceutically acceptable acid moieties. The same is true for the preparation of the medicament comprising the preparation of the salt, and optionally one or more other therapeutically useful substances together with one or more therapeutically inert carriers in a gallenose dosage form.

According to the present invention, compounds of formula (IA) or (IB) and pharmaceutically acceptable salts thereof are diseases based on adenosine receptor antagonist activity such as Alzheimer's disease, Parkinson's disease, Huntington's disease, neuroprotection, schizophrenia, Useful for inhibiting or preventing anxiety, pain, respiratory deficiency, depression, ADHD, amphetamines, cocaine, opioids, ethanol, nicotine, cannabinoids or drug addiction, or asthma, allergic reactions, hypoxia, ischemia, seizures, substance abuse, or It is useful as a sedative, muscle relaxant, antipsychotic, antiepileptic, anticonvulsant, and cardioprotectant for coronary artery disease and heart failure.

The most preferred indication according to the invention is the treatment or prevention of conditions including central nervous system abnormalities, for example Parkinson's disease, neuroprotection or certain depressive disorders.

The dosage can vary within wide limits and, of course, must be adjusted to the individual needs in each particular case. For oral administration, the dosage for an adult may be about 0.01 to about 1000 mg of the compound of formula (I) or a corresponding amount thereof in a pharmaceutically acceptable salt per day. The daily dose may be administered in a single dose or in divided doses and the upper limit may also be exceeded if indicated as indicated.

Tablet formulations (wet Granulation )

Manufacturing procedure

1. Mix items 1, 2, 3 and 4 and granulate with purified water.

2. Dry the granules at 50 ° C.

3. Pass the granules through a suitable grinding device.

4. Add item 5 and mix for 3 minutes; Press on a suitable press.

Capsule Formulation

Manufacturing procedure

1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add items 4 and 5 and mix for 3 minutes.

3. Fill into a suitable capsule.

The following preparations and examples illustrate the invention and do not limit the scope of the invention.

Example  One

2-([2-Methoxy-ethyl) -methyl-amino] -methyl) -3-methyl-3H-imidazole-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazole 2-yl) -amide

Tertiary butyllithium in a solution of 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine (220 mg, 0.83 mmol) in anhydrous tetrahydrofuran (10 ml) at −70 ° C. The solution (1.1 ml of 1.5 M solution in pentane, corresponding to 1.65 mmol) was added slowly and the remaining suspension was slowly warmed to about -30 ° C. At this time, 2-([(2-methoxy-ethyl) -methyl-amino] -methyl) -3-methyl-3H-imidazole-4-carboxylic acid phenyl ester (252 mg, 0.83) in tetrahydrofuran (4 ml) Mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was treated with saturated aqueous ammonium chloride solution (10 ml) followed by ethyl acetate (20 ml) and the resulting precipitate was collected. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were extracted twice with water, dried over magnesium sulfate and evaporated to dryness to yield another batch of crude product. Flash-chromatography (trichloromethane eluent containing 30% ethyl acetate) on silica gave the title compound as a white solid (31% yield). MS: m / e = 475 (M + H ⁺ ), mp 176-178 ° C.

The compounds of Examples 2-7 were prepared according to the general method of Example 1.

Example 2

2-Dimethylaminomethyl-3-methyl-3H-imidazole-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide

The title compound, using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 2-dimethylaminomethyl-3-methyl-3H-imidazole-4-carboxylic acid phenyl ester Was obtained as a gray solid (49% yield). MS: m / e = 431 (M + H ⁺ ), mp 229-231 ° C.

Example 3

3-Methyl-2-morpholin-4-ylmethyl-3H-imidazole-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide

4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 3-methyl-2-morpholin-4-ylmethyl-3H-imidazole-4-carboxylic acid phenyl ester The title compound was obtained as a gray solid (21% yield). MS: m / e = 473 (M + H ⁺ ), mp 244-246 ° C.

Example 4

3-Methyl-2-pyrrolidin-1-ylmethyl-3H-imidazol-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide

4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 3-methyl-2-pyrrolidin-1-ylmethyl-3H-imidazole-4-carboxylic acid phenyl ester The title compound was obtained as a gray solid (76% yield). MS: m / e = 457 (M + H ⁺ ), mp 255 ° C.

Example 5

1- (2-Pyrrolidin-1-yl-ethyl) -1H-pyrazole-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide

4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 1- (2-pyrrolidin-1-yl-ethyl) -1H-pyrazole-4-carboxylic acid ethyl ester Using, the title compound was obtained as a white solid (13% yield). MS: m / e = 457 (M + H ⁺ ), mp 190-192 ° C.

Example 6

1- (2-Dimethylamino-ethyl) -1 H-pyrazole-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide

4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 1- (2-dimethylamino-ethyl) -1H-pyrazole-4-carboxylic acid phenyl ester The title compound was obtained as white crystals (54% yield). MS: m / e = 431 (M + H ⁺ ), mp 203-205 ° C.

Example 7

1- (2-Molinolin-4-yl-ethyl) -1 H-pyrazole-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide

4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 1- (2-morpholin-4-yl-ethyl) -1H-pyrazole-4-carboxylic acid phenyl ester The title compound was obtained as white crystals (42% yield). MS: m / e = 473 (M + H ⁺ ), mp 204-207 ° C.

Example 8

1- (2-Methoxy-ethyl) -1 H-pyrazole-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide

Title compound, using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 1- (2-methoxy-ethyl) -1H-pyrazole-4-carboxylic acid phenyl ester Was obtained as pale yellow crystals (43% yield). MS: m / e = 418 (M + H ⁺ ), mp 191-193 ° C.

Example 9

2-Methoxymethyl-3-methyl-3H-imidazol-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide

The title compound was prepared using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 2-methoxymethyl-3-methyl-3H-imidazole-4-carboxylic acid phenyl ester. Obtained as white crystals (48% yield). MS: m / e = 418 (M + H ⁺ ), mp 242-245 ° C.

Intermediate

Example 10

2-([(2-Methyl-ethyl) -methyl-amino] -methyl) -3-methyl-3H-imidazole-4-carboxylic acid phenyl ester

1- (2-[(2-methoxy-ethyl) -methyl-amino] -ethyl) -1 H-pyrazole-4-carboxylic acid (467 mg, 1.54 in dimethylformamide (8 ml) under argon at 0 ° C. Mmol) and 4-dimethylaminopyridine (94 mg, 0.77 mmol) and bromine-tripyrrolidinophosphonium-hexafluorophosphate in dimethylformamide (8 ml) in a solution of phenol (145 mg, 1.54 mmol) A solution of part (790 mg, 0.70 mmol) was added followed by triethylamine (0.65 ml, 4.6 mmol). After 48 hours at ambient temperature, the reaction mixture was treated with saturated aqueous ammonium chloride (25 ml) and extracted three times with ethyl acetate (25 ml each). The combined organic layers were dried over magnesium sulfate and evaporated to dryness. Flash chromatography (silica, dichloromethane eluent containing 4% methanol) gave the title compound as a colorless oil (55% yield). MS: m / e = 304 (M + H ⁺ ).

The compounds of Examples 11-16 were prepared according to the general method of Example 10.

Example 11

2-dimethylaminomethyl-3-methyl-3H-imidazole-4-carboxylic acid phenyl ester

Using 2-dimethylaminomethyl-3-methyl-3H-imidazole-4-carboxylic acid, the title compound was obtained in light brown wax (43% yield). MS: m / e = 260 (M + H ⁺ ).

Example 12

3-Methyl-2-morpholin-4-ylmethyl-3H-imidazole-4-carboxylic acid phenyl ester

Using 3-methyl-2-morpholin-4-ylmethyl-3H-imidazole-4-carboxylic acid, the title compound was obtained as a colorless wax (40% yield). MS: m / e = 302 (M + H ⁺ ).

Example 13

3-Methyl-2-pyrrolidin-1-ylmethyl-3H-imidazole-4-carboxylic acid phenyl ester

Using 3-methyl-2-pyrrolidin-1-ylmethyl-3H-imidazole-4-carboxylic acid, the title compound was obtained in brown oil (22% yield). MS: m / e = 286 (M + H ⁺ ).

Example 14

1- (2-dimethylamino-ethyl) -1H-pyrazole-4-carboxylic acid phenyl ester

Using 1- (2-dimethylamino-ethyl) -1H-pyrazole-4-carboxylic acid, the title compound was obtained as a colorless liquid (56% yield). MS: m / e = 260 (M + H ⁺ ).

Example 15

1- (2-morpholin-4-yl-ethyl) -1H-pyrazole-4-carboxylic acid phenyl ester

Using 1- (2-morpholin-4-yl-ethyl) -1H-pyrazole-4-carboxylic acid, the title compound was obtained as a white solid (33% yield). MS: m / e = 302 (M + H ⁺ ), mp 73-76 ° C.

Example 16

1- (2-methoxy-ethyl) -1H-pyrazole-4-carboxylic acid phenyl ester

Using 1- (2-methoxy-ethyl) -1H-pyrazole-4-carboxylic acid, the title compound was obtained as a colorless oil (55% yield). MS: m / e = 247 (MH ⁺ ).

Example 17

2-methoxymethyl-3-methyl-3H-imidazole-4-carboxylic acid phenyl ester

Using 2-methoxymethyl-3-methyl-3H-imidazole-4-carboxylic acid, the title compound was obtained as a light yellow solid (39% yield). MS: m / e = 247 (MH ⁺ ), mp 54-58 ° C.

Example 18

2-Chloromethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester hydrochloride

A solution of 2-hydroxymethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester (250 mg, 1.5 mmol) in ethyl acetate / methanol (6 ml, 1: 1) was used with an ether solution excess of hydrogen chloride To hydrochloride. After evaporation, the light brown residue was treated with thionyl chloride (1.1 ml, 15 mmol) and stirred for 0.5 h. After evaporation, the title compound was obtained as a brown solid (100% yield). MS: m / e = 189 (M + H ⁺ ), mp 106-108 ° C.

Example 19

2-hydroxymethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester

Suspension of 3-methyl-3H-imidazole-4-carboxylic acid methyl ester (4.0 g, 29 mmol) and paraformaldehyde (18 g, equivalent to 570 mmol) in methanol (40 ml) in a closed vessel at 135 ° C. for 6.0 hours. Heated during. After cooling to ambient temperature, the solution was evaporated to dryness. Flash chromatography (silica, dichloromethane eluent containing 5% methanol) gave the title compound as white crystals (56% yield). MS: m / e = 171 (M + H ⁺ ), mp 145-147 ° C.

Example 20

2-methoxymethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester

A solution of 2-hydroxymethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester (250 mg, 1.5 mmol) in dimethylformamide (10 ml) was dissolved in sodium hydride (71 mg, 60% dispersion in mineral oil). , 1.8 mmol) and successively treated with dimethyl sulfate (0.17 ml, 1.8 mmol) after 0.5 h. After 1 hour at ambient temperature, the volatile components were removed in vacuo, the residue was dissolved in ethyl acetate (20 ml) and water (20 ml) and the phases separated. The aqueous phase was extracted twice with ethyl acetate (20 ml each) and the combined organic layers were dried over magnesium sulfate and evaporated to dryness. Flash chromatography (silica, dichloromethane eluent containing 4% methanol) gave the title compound as white crystals (42% yield). MS: m / e = 185 (M + H ⁺ ), mp 74-77 ° C.

Example 21

3-Methyl-2-pyrrolidin-1-ylmethyl-3H-imidazole-4-carboxylic acid methyl ester

2-chloromethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester hydrochloride (224 mg, 1 mmol) was dissolved in pyrrolidine (2.3 ml, 28 mmol) and stirred at ambient temperature for 45 minutes to give the title The compound was obtained as a pale yellow oil. After evaporation to dryness, the residue was dissolved in ethyl acetate and saturated aqueous sodium carbonate (20 ml) and the phases separated. The aqueous phase was extracted twice with ethyl acetate (20 ml each) and the combined organic layers were dried over magnesium sulfate and evaporated to dryness. Flash chromatography (silica, eluent, dichloromethane: methanol 19: 1) gave the title compound as a pale yellow oil (61% yield). MS: m / e = 224 (M + H ⁺ ).

The compounds of Examples 22-24 were prepared according to the general method of Example 21.

Example 22

3-Methyl-2-morpholin-4-ylmethyl-3H-imidazole-4-carboxylic acid methyl ester

Using 2-chloromethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester hydrochloride and morpholine, the title compound was obtained as a light brown solid (> 98% yield). MS: m / e = 240 (M + H ⁺ ).

Example 23

2-([(2-methoxy-ethyl) -methyl-amino] -methyl) -3-methyl-3H-imidazole-4-carboxylic acid methyl ester

Using 2-chloromethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester hydrochloride and (2-methoxy-ethyl) -methyl-amine, the title compound was obtained as a light brown viscous oil (92% yield). Obtained. MS: m / e = 242 (M + H ⁺ ).

Example 24

2-dimethylaminomethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester

Using 2-chloromethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester hydrochloride and dimethylamine (33% solution in ethanol), the title compound was obtained as a brown viscous oil (85% yield). . MS: m / e = 198 (M + H ⁺ ).

Example 25

2-([(2-methoxy-ethyl) -methyl-amino] -methyl) -3-methyl-3H-imidazole-4-carboxylic acid

2-([(2-methoxy-ethyl) -methyl-amino] -methyl) -3-methyl-3H-imidazole-4-carboxylic acid methyl ester (380 mg, 1.58 mmol) was dissolved in methanol (4.5 ml) And treated with water (0.39 ml) and lithium hydroxide monohydrate (80 mg, 1.89 mmol) and stirred at ambient temperature for 18 hours. The reaction mixture was carefully acidified with IN hydrochloric acid at 0 ° C. and evaporated to dryness. The title compound was obtained in a mixture with lithium chloride and used without further purification. Light brown solid (> 98% yield by 1 H-NMR). MS: m / e = 226 (MH ⁺ ).

The compounds of Examples 26-28 were prepared according to the general method of Example 25.

Example 26

2-Dimethylaminomethyl-3-methyl-3H-imidazole-4-carboxylic acid

Using 2-dimethylaminomethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester, the title compound was obtained as a light brown solid (> 98% yield by 1H-NMR). MS: m / e = 182 (MH ⁺ ).

Example 27

3-Methyl-2-pyrrolidin-1-ylmethyl-3H-imidazole-4-carboxylic acid

Using 3-methyl-2-pyrrolidin-1-ylmethyl-3H-imidazole-4-carboxylic acid methyl ester, the title compound was obtained as a brown wax (> 98% yield by 1 H-NMR). MS: m / e = 208 (MH ⁺ ).

Example 28

3-Methyl-2-morpholin-4-ylmethyl-3H-imidazole-4-carboxylic acid

Using 3-methyl-2-morpholin-4-ylmethyl-3H-imidazole-4-carboxylic acid methyl ester, the title compound was obtained as a light brown solid (> 98% yield by 1H-NMR). MS: m / e = 224 (MH ⁺ ).

Example 29

2-methoxymethyl-3-methyl-3H-imidazole-4-carboxylic acid

Using 2-methoxymethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester, the title compound was obtained as a brown solid and used without further characterization.

Example 30

1- (2-morpholin-4-yl-ethyl) -1H-pyrazole-4-carboxylic acid ethyl ester

1H-pyrazole-4-carboxylic acid (300 mg, 2.1 mmol), 4- (2-chloroethyl) morpholine (822 mg, 4.3 mmol) and potassium carbonate (1.2 g, 8.6 mmol) were added to dimethylformamide (12 ml) and stirred at 75 ° C. for 6.5 h. After another 18 hours at ambient temperature, the reaction mixture was treated with water (25 ml) and extracted four times with ethyl acetate (25 ml each). The combined organic layers were extracted four times with water, dried over magnesium sulfate and evaporated in vacuo. Flash chromatography (silica, dichloromethane eluent containing 4% methanol) gave the title compound as a colorless liquid (70% yield). MS: m / e = 254 (M + H ⁺ ).

The compounds of Examples 31 to 32 were prepared according to the general method of Example 30.

Example 31

1- (2-dimethylamino-ethyl) -1H-pyrazole-4-carboxylic acid ethyl ester

Using 1H-pyrazole-4-carboxylic acid and (2-chloro-ethyl) -dimethyl-amine, the title compound was obtained as a colorless liquid (72% yield). MS: m / e = 212 (M + H ⁺ ).

Example 32

1- (2-Pyrrolidin-1-yl-ethyl) -1H-pyrazole-4-carboxylic acid ethyl ester

Using 1H-pyrazole-4-carboxylic acid and 1- (2-chloro-ethyl) -pyrrolidine, the title compound was obtained in light brown oil (65% yield). MS: m / e = 238 (M + H ⁺ ).

Example 33

1- (2-methoxy-ethyl) -1H-pyrazole-4-carboxylic acid ethyl ester

Using 1H-pyrazole-4-carboxylic acid and 2-bromoethyl methyl ether, the title compound was obtained as a colorless oil (67% yield). MS: m / e = 199 (M + H ⁺ ).

Example 34

1- (2-Dimethylamino-ethyl) -1 H-pyrazole-4-carboxylic acid

2-([(2-methoxy-ethyl) -methyl-amino] -methyl) -3-methyl, using 1- (2-dimethylamino-ethyl) -1H-pyrazole-4-carboxylic acid ethyl ester The title compound was prepared in the same manner as described for -3H-imidazole-4-carboxylic acid. White solid (> 98% yield by ¹ H-NMR). MS: m / e = 184 (M + H ⁺ ).

Example 35

Using 1- (2-morpholin-4-yl-ethyl) -1H-pyrazole-4-carboxylic acid ethyl ester, the title compound was obtained as a pale yellow solid and used without further characterization. MS: m / e = 224 (MH ⁺ ).

Example 36

1- (2- Methoxy -Ethyl) -1H- Pyrazole -4- Carboxylic acid

Using 1- (2-methoxy-ethyl) -1H-pyrazole-4-carboxylic acid ethyl ester, the title compound was obtained as a colorless oil and used without further characterization. MS: m / e = 169 (MH ⁺ ).

Claims (18)

A compound of formula (IA) or (IB), or a pharmaceutically acceptable acid addition salt thereof: Formula IA

Formula IB

Where R ¹ and R ² are independently of each other C ₁ -C ₆ alkyl or — (CH ₂ ) _m —OC ₁ -C ₆ alkyl, or together with the N atom to which they are attached form morpholine or pyrrolidine; R ³ is hydrogen or C ₁ -C ₆ alkyl; R ⁴ is C ₁ -C ₆ alkyl; hetaryl is 3H-imidazole-2,4-diyl or 1H-pyrazole-1,4-diyl; n is 1 or 2; m is 1 or 2. The method of claim 1, A compound of formula (IA) or a pharmaceutically acceptable acid addition salt thereof. The method of claim 2, A compound wherein the hetaryl group is 3H-imidazole-2,4-diyl or a pharmaceutically acceptable acid addition salt thereof. The method of claim 3, wherein 2-([(2-Methoxy-ethyl) -methyl-amino] -methyl) -3-methyl-3H-imidazole-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothia Zol-2-yl) -amide, 2-dimethylaminomethyl-3-methyl-3H-imidazol-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide, 3-Methyl-2-morpholin-4-ylmethyl-3H-imidazole-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide, or 3-Methyl-2-pyrrolidin-1-ylmethyl-3H-imidazol-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide Or pharmaceutically acceptable acid addition salts thereof. The method of claim 2, A compound wherein the hetaryl group is 1H-pyrazole-1,4-diyl or a pharmaceutically acceptable acid addition salt thereof. The method of claim 5, wherein 1- (2-Pyrrolidin-1-yl-ethyl) -1H-pyrazole-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide, 1- (2-Dimethylamino-ethyl) -1 H-pyrazole-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide, or 1- (2-morpholin-4-yl-ethyl) -1H-pyrazole-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide Or pharmaceutically acceptable acid addition salts thereof. The method of claim 1, A compound of formula (IB) or a pharmaceutically acceptable acid addition salt thereof. The method of claim 7, wherein A compound wherein the hetaryl group is 3H-imidazole-2,4-diyl or a pharmaceutically acceptable acid addition salt thereof. The method of claim 8, 2-Methoxymethyl-3-methyl-3H-imidazole-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide, or a pharmaceutically acceptable salt thereof Acceptable acid addition salts. The method of claim 7, wherein A compound wherein the hetaryl group is 1H-pyrazole-1,4-diyl or a pharmaceutically acceptable acid addition salt thereof. The method of claim 10, 1- (2-methoxy-ethyl) -1H-pyrazole-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide or a pharmaceutical thereof Acceptable acid addition salts. (a) A solution of tertiary butyllithium in pentane was added to a solution of the compound of formula II in tetrahydrofuran at −70 ° C. and the suspension was warmed to −30 ° C., followed by formula III in tetrahydrofuran Solution was added and the mixture was stirred at room temperature for 1 hour, and the reaction mixture was treated with saturated ammonium chloride solution followed by ethyl acetate to obtain a compound of formula (IA); or (a ') A solution of tertiary butyllithium in pentane was added to a solution of the compound of formula II in tetrahydrofuran at -70 ° C and the suspension was warmed to -30 ° C, and the following formula in tetrahydrofuran A solution of IV was added and the mixture was stirred at room temperature for 1 hour, and the reaction mixture was treated with saturated ammonium chloride solution followed by ethyl acetate to obtain a compound of formula IB If desired, a process for preparing a compound of formula (IA) or (IB) as defined in claim 1 comprising converting the obtained compound to a pharmaceutically acceptable acid addition salt: Formula II

Formula III

Formula IA

Formula IV

Formula IB

In the above, R ¹ , R ² , R ³ , R ⁴ , hetaryl and n have the meanings indicated in claim 1. delete 12. Alzheimer's disease, Parkinson's disease, Huntington's disease, neuroprotection, schizophrenia, anxiety, pain, respiratory deficiency, containing at least one compound as claimed in claim 1 and a pharmaceutically acceptable excipient, Treats depression, drug deficit hyperactivity disorder (ADHD), drug addictions such as amphetamines, cocaine, opioids, ethanol, nicotine, cannabinoids, or asthma, allergic reactions, hypoxia, ischemia, seizures and substance abuse A medicament used for or used as a sedative, muscle relaxant, antipsychotic, antiepileptic, anticonvulsant, and cardioprotective against coronary artery disease and heart failure. delete delete delete delete