JPH0753378A - Thiazole derivative, its preparation and pharmaceutical composition containing said derivative, which is applied to disease or symptom in which leukotriene intervenes - Google Patents

Abstract

PURPOSE: To obtain a new thiazole derivative having inhibitory activity against enzyme 5-LO and leukotriene biosynthesis, high in safety, and useful for treating allergic diseases, psoriasis, asthma, cardiovascular diseases, cerebrovascular diseases, inflammatory diseases, bone metabolism-involved diseases, etc. CONSTITUTION: This new compound is shown by formula I [Q is 2-oxo-1,2,3,4- tetrahydroquinolin-6-yl or 2-oxo-1,2-dihydroquinolin-6-yl; X<1> is thio, sulfinyl or sulfonyl; Ar is thiazole-diyl; R<1> is a 1-4C alkyl, 3-4C alkenyl, etc.; R<2> and R<3> are joined together to form A<2> -X<2> -A<3> (A<2> and A<3> are each a five- or six- membered ring or 1-3C alkylene; X<2> is oxy)] e.g.(2S,4R)-4-methoxy-2- methyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thiazo l-5- yl]tetrahydropyran}. The compound of formula I is obtained by reaction of a compound of the formula Q-X<1> -H with a compound of formula II (Z is an eliminable group).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a thiazole derivative, particularly a thiazole derivative which is an inhibitor of the enzyme 5-lipoxygenase (hereinafter referred to as 5-LO). Furthermore, the present invention relates to the above-mentioned method for producing a thiazole derivative and a novel pharmaceutical composition containing the thiazole derivative. Furthermore, according to the present invention, the arachidonic acid 5-
Also included is the use of the above thiazole derivatives in the treatment of various inflammatory and / or allergic diseases involving the direct or indirect products of the catalytic oxidation by LO and the manufacture of new medicaments for this use.

[0002]

As mentioned above, the thiazole derivative described below is an inhibitor of 5-LO, and this enzyme oxidizes arachidonic acid and undergoes a cascade process to obtain physiologically active leukotrienes such as leukotriene B.
₄ (LTB ₄ ), and a peptide-lipid leukotriene,
For example, it is known to be involved in catalysis to give leukotriene C ₄ (LTC ₄ ) and leukotriene D ₄ (LTD ₄ ) and various metabolites.

The biosynthetic relationship and physiological properties of this leukotriene are described in GW Taylor and S. R. Clarke in Tr.
ends in Pharmacological Sciences, 1986, 7, 100-103
Are summarized in. The leukotrienes and their metabolites are associated with a variety of diseases such as a variety of inflammatory and allergic diseases such as joint inflammation (especially rheumatoid arthritis, osteoarthritis and gout), gastrointestinal tract inflammation (especially inflammatory bowel disease, Occurrence and progression of ulcerative colitis and gastritis), skin disorders (especially psoriasis, eczema, dermatitis), eye disorders (especially allergic conjunctivitis and uveitis) and respiratory disorders (asthma, bronchitis and allergic rhinitis). , And a variety of cardiovascular and cerebrovascular diseases such as myocardial infarction, atherosclerotic plaque, hypertension, platelet aggregation, angina, seizures, reperfusion injury, such as burns, toxicosis or the formation of shock symptoms and trauma after surgery. , Including stenotic and peripheral vascular disease, and various disorders of, for example, bone metabolism, such as bone coarseness Disease (including osteoporosis after senile or 閉月 through life), Paget's disease, bone dislocation, hypercalcemia, hyperparathyroidism,
It is associated with the development and progression of abnormal changes in bone metabolism with osteosclerosis, osteopetrosis and periodontitis, and rheumatoid arthritis and osteoarthritis. Moreover, the leukotrienes are mediators of inflammatory diseases due to their ability to regulate lymphocyte and leukocyte function. Other physiologically active metabolites of arachidonic acid, such as prostaglandins and thromboxane, are produced by the action of the enzyme cyclooxygenase on arachidonic acid.

European Patent Application Nos. 0385662 and 0
No. 420511 describes certain heterocyclic derivatives having inhibitory properties for 5-LO. In particular, European Patent Application No. 0462812 describes 5
-A heterocyclic derivative having inhibitory properties for LO. This heterocyclic derivative described in the above specification has the formula:

[0005]

[Chemical 6]

Wherein Ar ² represents a 5-membered heterocyclic group selected from nitrogen, oxygen and sulfur such as pyrrolediyl, furandyl and thiophenediyl. In particular, the compounds described above include the following thiophenediyl derivatives: 4-methoxy-4-
[5- (1-Methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio) -thien-2-yl] tetrahydropyran (Example 7 of the above specification); and (2S, 4R) -4-methoxy-2-methyl-4-
[5- (1-methyl-2-thioxo-1,2,3,4-
Tetrahydroquinolin-6-ylthio) -thien-2-
Il] tetrahydropyran (Example 12 of the above specification).
European Patent Application No. 0462812 describes Ar ²
However, compounds of 5-membered heterocyclic groups containing two heteroatoms selected from nitrogen, oxygen and sulfur are not described. In particular, a compound in which Ar ² is a thiazolediyl group is not described.

Further, European Patent Application No. 0462812
Certain compounds described in the
-induction). Thus, repeated administration of this compound to warm-blooded animals results in increased efficiency of the animal's liver enzymes to metabolize this compound. This result is due to the compound as measured by, for example, the reduction in the maximum concentration achieved (C max) or by the area under the curve (AUC) of the plot of the concentration of the compound in the bloodstream against the time after administration, for example. Repeated administration, as described above, results in a reduction in the amount of this compound present in the bloodstream of the animal, as indicated by a reduced effect on the animal. The compound 4-methoxy-4- [5- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio) thien-2-yl] tetrahydropyran is a self-induced undesired It has characteristics.

Certain compounds described in European Patent Application No. 0462812 are amorphous, for example oily or gummy or are isolated as foams. Such an amorphous compound is undesirable when considering the manufacture, purification, analysis, handling and preparation of large amounts of this compound. This compound (2S, 4R) -4-
Methoxy-2-methyl-4- [5- (1-methyl-2-
Thioxo-1,2,3,4-tetrahydroquinoline-6
-Ylthio) thien-2-yl] tetrahydropyran has the undesirable properties of viscous oils.

It has been found that certain thiazole derivatives are advantageous inhibitors of the enzyme 5-LO and leukotriene biosynthesis. Such compounds are, for example, allergic conditions mediated alone or in part by one or more leukotrienes, psoriasis, asthma, cardiovascular and cerebrovascular diseases, inflammatory and arthritic conditions, and / or bone metabolism. It is useful as a therapeutic agent in the treatment of diseases.

[0010]

According to the invention, the formula I:

[0011]

[Chemical 7]

[Wherein Q is 2-oxo-1,2,3,4
-Tetrahydroquinolin-6-yl or 2-oxo-
1,2-dihydroquinolin-6-yl, which has a C ₁ -C ₄ alkyl substituent at the 1-position nitrogen atom; X ¹
Represents thio, sulfinyl or sulfonyl; Ar represents thiazolediyl; R ¹ is C ₁ -C ₄ alkyl, C ₃
~ C ₄ alkenyl or C ₃ -C ₄ alkynyl; R ²
And R ³ together form a group of —A ² —X ² —A ³ —, which group together with the carbon atom to which A ² and A ³ connect, is a 5 or 6 membered ring atom. And A ² and A ³ may be the same or different and each represents C ₁ -C ₃ alkylene, X ² represents oxy,
This ring has one or two C ₁ -C ₄ alkyl substituents] or a pharmaceutically acceptable salt thereof.

As used herein, the general term "alkyl"
Includes both straight chain and branched chain alkyl groups. However, for individual alkyl groups such as "propyl," only the straight-chain one is specified, and for individual branched-chain alkyl groups such as "isopropyl," only the branched-chain one is specified. Similar rules apply for other general terms.

In addition, certain compounds of formula I above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the present invention, in this sense, inhibiting 5-LO. It is understood to include certain optically active or racemic forms having the properties of Synthesis of optically active forms can be accomplished by standard techniques of organic chemistry known in the art, such as synthesis from optically active starting materials or resolution of racemic forms.

Suitable values for the general terms reported above include those set out below.

A preferred value for the C ₁ -C ₄ alkyl substituent present on Q is, for example, methyl, ethyl or propyl.

When Ar is thiazolediyl, suitable values are, for example, 2,4-thiazolediyl, 2,5-
It is thiazolediyl.

A suitable value for R ¹ is C ₁ -C ₄ alkyl, for example methyl, ethyl or propyl, and for C ₃ -C ₄ alkenyl, for example allyl, C ₃ -C. _When it is ₄ alkynyl, for example, 2
-Propynyl.

R ² and R ³ together form the formula: -A ^2-
X ² —A ³ — forms a group which, together with the carbon atom to which A ² and A ³ are attached, forms the same or a ring having 5 or 6 membered ring atoms. A suitable value for A ² or A ³ , which may be different, is C ₁ -C ₃ alkylene, respectively, for example methylene, ethylene or trimethylene. Suitable values for the C ₁ -C ₄ alkyl substituents which may be present on the 5- or 6-membered ring are, for example, methyl and ethyl.

Suitable pharmaceutically acceptable salts of the compounds of the invention are, for example, acid addition salts of the compounds of the invention which are sufficiently basic, for example inorganic or organic acids, for example hydrochloric acid, hydrobromic acid, Acid addition salts with sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of the compounds of the invention which are sufficiently basic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts or Organic bases that provide physiologically tolerable cations, such as methylamine, dimethylamine, trimethylamine, piperidine,
It is a salt with morpholine or tris- (2-hydroxyethyl) amine.

A particular compound of the invention is the variable Q,
Includes thiazole derivatives of formula I or pharmaceutically acceptable salts thereof, wherein X ¹ , Ar, R ¹ , R ² and R ³ represent values as described above or below in the art relating to the particular compound of the invention. : (A) Q is 1-methyl-2-oxo-1,2,3,4
- represents a-tetrahydroquinolin-6-yl; (b) X ¹ represents a thio or sulphonyl; (c) Ar is X ¹ with 2,4-thiazolediyl (2-position
(Bonded to a group) (d) Ar is 2,5-thiazoldiyl (X ¹
(E) Ar is 2,5-thiazoldiyl (X ¹ at the 5-position)
(F) R ¹ represents a methyl group; (g) R ² and R ³ are taken together to form a compound represented by the formula: —A ² —X ²
A group of --A ^3-, which together with the carbon atom to which A ² and A ³ are bonded, represents a ring having a 5 or 6 membered ring atom, wherein A ² is methylene. Or represents ethylene, A ³ represents ethylene, X ² represents oxy,
The ring can have a methyl substituent in the α position relative to X ² .

Preferred compounds of the present invention are wherein Q represents 1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl; X ¹ represents thio or sulfonyl; Ar is 2 , 5-thiazoldiyl (bonded to the X ¹ group at the 2-position), R ¹ represents methyl; and R ² and R
³ together form a group of the formula: —A ² —X ² —A ³ —, which group together with the carbon atom to which A ² and A ³ are attached, has a 6-membered ring atom. Represents a ring having, in which case A ²
And A ³ each represents ethylene, X ² represents oxy, and the ring has a thiazole derivative of formula I or a pharmaceutically acceptable salt thereof which may have a methyl substituent in the α-position to X ² . It consists of salt.

Another preferred compound of the invention is that Q represents 1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl; X ¹ represents thio or sulfonyl; Ar represents 2,5-thiazoldiyl (bonded to the X ¹ group at the 2-position), R ¹ represents methyl; and R ²
And R ^{3 taken} together are of the formula: —CH ₂ CH ₂ OCH
It consists of a thiazole derivative of the formula I forming a (CH ₃ ) CH ₂ — group or a pharmaceutically acceptable salt thereof.

Particularly advantageous compounds of the invention are the compounds of formula I: (2S, 4R) -4-methoxy-2-methyl-4- [2
-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio) thiazol-5-yl] tetrahydropyran.

In another embodiment of the invention, it has been found that certain compounds of the invention do not actually possess the undesired self-inducing properties. Such compounds are
It does not show the drawbacks caused by autoinduction and is particularly effective in the treatment of various diseases in warm-blooded animals, such as inflammatory and / or allergic diseases. Thus, for example, the evaluation of pharmacological and toxicological data is further complicated if the test compound is shown to have a significant degree of autoinduction. In addition to autoinduction, general induction of enzymes can be expected, which may exhibit undesired effects, such as a deleterious increase in the rate of metabolism of all drugs with which it is co-administered.

In another embodiment of the invention, it has been found that certain compounds of the invention are crystalline. Such compounds are important when their large scale production is required. Purification, analysis and handling of the material is easy if it is formed in crystalline form. For example, it is known that solvent residues are difficult to remove from amorphous or oily materials. Furthermore, the method of preparing a pharmaceutical composition of crystalline material is a common method. The composition may be in a form suitable for oral use eg tablets or capsules; or for administration eg by inhalation eg finely divided powders or microcrystalline forms. Such a choice for the preparation of this material is not possible if it is formed in an oily state.

The compounds of the invention consisting of the thiazole derivative of formula I or a pharmaceutically acceptable salt thereof can be prepared by any known method suitable for the preparation of structurally similar compounds. Such a method provides another embodiment of the present invention and is illustrated by the examples shown below, where Q, X ¹ , Ar,
R ¹ , R ² and R ³ represent all of the above.

(A) The formula: usually in the presence of a suitable base:
A compound of Q-X ¹ -H and a formula II:

[0029]

[Chemical 8]

Coupling with a compound of the formula [wherein Z represents a removable group].

Suitable releasable groups Z are, for example, halogeno or sulphonyloxy groups, for example fluoro, chloro, bromo, iodo, methane-sulphonyloxy or toluene-4-sulphonyloxy groups.

Suitable bases for this coupling reaction are, for example, alkali metal or alkaline earth metal carbonates, C ₁ -C ₄ alkoxides, hydroxides or hydrides such as sodium carbonate, potassium carbonate, sodium ethoxide. , Potassium butoxide, lithium hydroxide,
Sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or an organometallic base, C ₁ -C ₄
Alkyl-lithium, for example n-butyllithium. This coupling reaction usually involves an inert solvent or diluent such as N, N-dimethylformamide, N, N.
-Dimethylacetamide, N-methylpyrrolidine-2-
It is carried out in the presence of on, dimethylsulfoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, for example at a temperature in the range 10 to 150 ° C, usually at or near 100 ° C.

Usually, this reaction is carried out with a suitable catalyst such as a metal catalyst such as palladium (0) or copper (I),
It can be carried out, for example, in the presence of tetrakis (triphenylphosphine) palladium, copper (I) chloride or copper (I) bromide.

The starting materials of formula Q-X ¹ -H and formula II can be obtained by standard methods of organic chemistry. The preparation of such starting materials is described in the non-limiting examples below. Alternatively, the required starting materials can be obtained using methods similar to those exemplified in the ordinary art of organic chemistry.

(B) A compound of the formula: QZ (wherein Z represents a removable group as described above) and a compound of the formula III: usually in the presence of a suitable base as described above.

[0036]

[Chemical 9]

Coupling with a compound of.

The coupling reaction is usually carried out in the presence of a suitable inert solvent as described above, for example 10 to 150.
It is carried out at a temperature in the range of 0 ° C, usually at or near 100 ° C. This reaction can usually be carried out in the presence of a suitable catalyst as described above.

The starting materials of formula: QZ and formula III are:
It can be obtained by standard methods of organic chemistry. Alternatively, the required starting materials can be obtained using methods similar to those exemplified in the ordinary art of organic chemistry. The disclosure of European Patent Application No. 0420511 relates to the production of particularly suitable starting materials.

(C) Formula: Q-X ¹ -Z (wherein Z represents a removable group as described above, or when X ¹ represents a thio group, Z represents the formula: Q-X ¹ A compound of formula IV:

[0041]

[Chemical 10]

Coupling with an organometallic reagent, wherein M represents an alkali metal or alkaline earth metal, such as lithium or calcium, or M represents the magnesium halide moiety of a conventional Grignard reagent.

This coupling reaction is usually carried out in a suitable inert solvent or diluent as described above, eg -80.
To + 50 ° C., usually at a temperature in the range of −80 ° C. to ambient temperature.

The preparation of the starting materials of formula: Q-X ¹ -Z and formula IV is obtained by standard methods of organic chemistry. Alternatively, the required starting materials can be obtained by methods similar to those described in the ordinary art of organic chemistry. The disclosure of the European patent application mentioned above relates to the production of particularly suitable starting materials.

(D) Usually, in the presence of a suitable base as described above, the formula V:

[0046]

[Chemical 11]

Alkylation of the compound of formula (I) with a compound of formula R ¹ -Z (wherein Z is a removable group as described above).

This alkylation reaction is usually carried out in a suitable inert solvent or diluent as described above, at -20 to +7.
It is carried out at a temperature in the range of 0 ° C., usually at or near ambient temperature.

The preparation of the starting material of formula V can be obtained by standard methods of organic chemistry. Alternatively, the required starting materials can be obtained using methods similar to those shown in the European patent application mentioned above.

(E) Alkylation of a compound of formula I, wherein Q has a hydrogen atom on an effective nitrogen atom as described above, for the preparation of a compound of formula I having an alkyl substituent on the effective nitrogen atom.

Suitable alkylating agents are, for example, all agents known in the process for the alkylation of available nitrogen atoms, for example alkyl halides in the presence of a suitable base as described above, for example C ₁ -C _4. Alkyl chloride, bromide or iodide. The alkylation reaction is preferably carried out with a suitable inert solvent or diluent, such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetone, 1,2-
10 in dimethoxyethane or tetrahydrofuran
It is carried out at a temperature in the range of to 150 ° C., usually at or near ambient temperature.

(F) Oxidation of a compound of formula I in which X ¹ represents a thio group, for the preparation of compounds of formula I in which X ¹ represents a sulfinyl or sulfonyl group.

Suitable oxidizing agents are, for example, all agents known in the art for the oxidation of thio to sulfinyl and / or sulfonyl, such as hydrogen peroxide, peracids (eg 3-chloroperoxybenzoic acid or peroxyacetic acid). , Gaseous oxygen in the presence of alkali metal peroxysulfates (eg potassium peroxymonosulfate), chromium trioxide or platinum. This oxidation is usually carried out under the mildest possible conditions with the required stoichiometric amount of oxidizing agent in order to reduce the risk of over-oxidation and damage to other functional groups. . In general, this reaction is
It is carried out in a suitable solvent or diluent, for example methylene chloride, chloroform, acetone, tetrahydrofuran or t-butyl methyl ether, at or near ambient temperature, that is to say in the range from 15 to 35 ° C. If compounds with sulfinyl groups are required, milder oxidizing agents, such as sodium or potassium metaperiodate, can also be used, usually in polar solvents such as acetic acid or ethanol. It was found that when a compound of formula I having a sulfonyl group is required, it can be obtained by oxidation of the corresponding sulfinyl compound as well as the corresponding thio compound.

If a pharmaceutically acceptable salt of a novel compound of formula I is required, it can be obtained, for example, by reacting the compound with a suitable acid or base using conventional methods. If an optically active form of the compound of formula I is required, it can be obtained by carrying out the process described above using optically active starting materials or by resolving the racemic form of the compound using conventional methods. You can

As mentioned above, the compounds of formula I
It is an inhibitor of LO. The effect of this inhibitor can be demonstrated using one or more of the standard methods described below: a) Test compound together with heparinized human blood prior to challenge with calcium ionophore A23187. Incubate the Young et alia (Prostagla
ndins, 1983, 26 (4), 605-613) using the protein-LTB ₄ conjugate produced by Carey and F.
order (F. Carey and RA Forder, Prostaglandins L
eukotriens Med., 1986, 22, 57; Prostaglandins, 198
4, 28, 666; Brit. J. Pharmacol. 1985, 84, 34P) using a specific radioimmunoassay.
An in vitro assay system that indirectly measures the inhibitory effect on 5-LO by measuring the amount of TB ₄ . The effect of test compounds on the enzyme cyclooxygenase, which is involved in other metabolic pathways for arachidonic acid and degrades prostaglandins, thromboxane and related metabolites, was described by Carey and Forder (supra). It can be measured simultaneously using a specific radioimmunoassay for thromboxane B ₂ (TxB ₂ ).
This test tested for 5-L in the presence of blood cells and proteins.
The effect of test compounds on O and cyclooxygenase is shown. This makes it possible to measure the selectivity of the inhibitory effect on 5-LO or cyclooxygenase.

B) administration of a solution of the test compound to a group of rats (usually orally as a suspension prepared when a solution of the test compound in dimethylsulfoxide is added to carboxymethylcellulose), blood collection, In vitro assay system of the variation of a) above, wherein heparin treatment, challenge with A23187, radioimmunoassay of LTB ₄ and TxB ₂ is performed. This test demonstrates the bioavailability of test compounds as inhibitors of 5-LO or cyclooxygenase.

C) An in vivo system which measures the effect of an orally administered test compound against the zymosan-induced release of LTB _{4 in} the air pouch occurring in the dorsal subcutaneous tissue of a group of male mice. The rat is anesthetized and an air pouch is formed by injecting sterile air (20 ml). A further injection of air (10 ml) is likewise made after 3 days. Six days after the first injection of air, the test compound is administered (usually orally as a prepared suspension when a solution of the test compound in dimethylsulfoxide is added to hydroxypropylmethylcellulose), followed by zymosan ( Intracapsular injection of 1% suspension in saline (1 ml). After 3 hours, the rats are killed, the air pouches are washed with saline and the specific radioimmunoassay described above is used to measure LTB ₄ in the wash. This test shows an inhibitory effect against 5-LO in an inflammatory environment.

The pharmacological properties of the compounds of formula I vary as expected with structural changes, but in general the compounds of formula I are prepared in one or more of the above tests a) to c) as follows: It has a 5-LO inhibitory effect at concentration or dose.

Test a): IC ₅₀ (LTB ₄ ) in the range of 0.01-40 μM IC ₅₀ (TxB ₂ ) in the range of 40-200 μM; Test b): Oral ED ₅₀ (LTB ₄ ) in the range of 0. 1-1
Within the range of 00 mg / kg; Study c): Oral ED ₅₀ (LTB ₄ ) eg 0.1-1
Within the range of 00 mg / kg.

In tests b) and / or c) there was no apparent toxicity or side effects even when the compound of formula I was administered at several times the minimal inhibitory dose or concentration.

Thus, by way of example, the compound (2S,
4R) -4-methoxy-2-methyl-4- [2- (1-
Methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio) thiazol-5-yl] tetrahydropyran showed an IC ₅₀ of 0.06 μM against LTB _{4 in} test a), the test LTB in c)
4 shows an ED ₅₀ of about 0.2 mg / kg.

These compounds are examples of compounds of the invention which have selective inhibitory properties for 5-LO as opposed to cyclooxygenase, which selective properties are often associated with cyclooxygenase inhibitors such as indomethacin. It is expected to result in improved therapeutic properties that reduce or eliminate gastrointestinal side effects.

According to another embodiment of the present invention, a thiazole derivative of formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier. A pharmaceutical composition is provided.

The composition is in a form suitable for oral use, eg tablets, capsules, aqueous or oily solutions,
Suspensions or emulsions; forms suitable for topical use, eg creams, ointments, gels or aqueous or oily solutions or suspensions; forms suitable for nasal use, eg olfactory, nasal sprays or drops Suitable for vaginal or rectal use, eg suppositories; suitable for administration by inhalation, eg finely divided powders eg dry powder, microcrystalline forms or liquid aerosols; suitable for sublingual or buccal use Any form, such as tablets or capsules; or any form suitable for parenteral application (intravenous, intraperitoneal, intramuscular, intravascular or infusion), such as sterile aqueous or oily solutions or suspensions. In general, the compositions described above may be manufactured in conventional manner using conventional excipients.

The amount of active ingredient (the thiazole derivative of formula I or a pharmaceutically acceptable salt thereof) in combination with one or more excipients to produce a single dosage form depends on the host treated and especially It needs to be changed depending on the administration route.
For example, a medicament intended for oral administration to humans will generally have a concentration of, for example, about 5-98% by weight of the total medicament.
It consists of 0.5 to 2 g of active ingredient in combination with a suitable and convenient amount of excipient which can vary in amount. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of active ingredient.

Another aspect of the present invention provides a thiazole derivative of formula I or a pharmaceutically acceptable salt thereof for use in a method for treating the human or animal body in the case of treatment. It

Furthermore, the present invention provides a disease or condition mediated alone or in part by one or more leukotrienes which comprises administering to a warm blooded animal in need of treatment an effective amount of the active ingredient as described above. Is a method of treating. Furthermore, the present invention provides the use of the active ingredient in the manufacture of a novel medicament for use in leukotriene mediated diseases or conditions.

The dose of a compound of formula I for therapeutic or prophylactic use will generally depend on the type and degree of symptoms, the age and sex of the animal or patient, and the route of administration.
Changes according to known medical principles. As mentioned above, the compounds of formula I show the metabolic effects of arachidonic acid produced by a linear (5-LO catalyzed) pathway, in particular leukotrienes, allergenicity and inflammation due to 5-LO mediated production. It is effective in treating sexual symptoms. As mentioned above, such conditions may include, for example, various diseases such as various inflammatory and allergic diseases such as joint inflammation (especially rheumatoid arthritis, osteoarthritis and gout), gastrointestinal tract inflammation (especially inflammation). Enteric diseases, ulcerative colitis and gastritis), skin diseases (especially psoriasis, eczema, dermatitis), eye diseases (especially allergic conjunctivitis and uveitis) and respiratory diseases (asthma, bronchitis and allergic rhinitis). Occurrence and progression of various cardiovascular and cerebrovascular diseases such as myocardial infarction, atherosclerotic plaque, hypertension, platelet aggregation, angina, seizures,
Vascular damage, including stenotic and peripheral vascular disease, in the formation of reperfusion injury, such as burns, poisoning or symptoms of shock after surgery and trauma, and various disorders of bone metabolism, such as osteoporosis (senile Or post-menopausal osteoporosis), Paget's disease, bone dislocation,
It is involved in the development and progression of hypercalcemia, hyperparathyroidism, osteosclerosis, osteopetrosis and periodontitis, and abnormal changes in bone metabolism with rheumatoid arthritis and osteoarthritis.

When using the compounds of formula I for therapeutic and prophylactic purposes, in general, the daily administration is for example 1 kg body weight.
The dose is given in the range of 0.5 mg to 75 mg per dose, and is given as distributed doses as needed. When using the parenteral route, low doses are generally administered. Thus, for example, for intravenous administration, for example, from 0.5 mg to 30 m / kg body weight.
Used in the range of g. Similarly, for administration by inhalation, for example, 0.5 mg to 25 per kg body weight
Used in the mg range.

The compounds of formula I are of primary value as therapeutic agents for use in warm-blooded animals, including humans,
This is useful where it is necessary to inhibit the enzyme 5-LO. Thus, this compound is useful as a pharmacological standard in the development of new biological tests and the search for new drugs.

Because of this effect on leukotriene production, the compounds of formula I have a certain cytoprotective effect, for example this compound is a nonsteroidal anti-inflammatory drug (NSAIA) which inhibits cyclooxygenase, such as indomethacin, acetylsalicylic acid. , Ibuprofen, sulindac, tolmetin and piroxicam are effective in reducing or suppressing some of the anti-gastrointestinal effects. In addition, the 5-LO inhibitor of formula I is
Administration with A results in a quantitative reduction in the latter drug required to produce a therapeutic effect, thereby reducing the potential for side effects. According to another embodiment of the present invention, the thiazole derivative of formula I or a pharmaceutically acceptable salt thereof as described above is treated with a non-steroidal anti-inflammatory drug which inhibits cyclooxygenase (for example as described above). , And a pharmaceutically acceptable diluent or carrier with or in admixture.

The cytoprotective effect of the compounds of formula I is demonstrated in a standard laboratory model which assesses the protection against indomethacin-induced or ethanol-induced ulcers in the gastrointestinal tract of the rat, for example.

The pharmaceutical products of the present invention may additionally contain one or more therapeutic or prophylactic agents known for the evaluation of diseases under treatment. Thus, for example, known platelet aggregation inhibitors, low lipid agents (hypolioidemic agents),
Antihypertensive agents, beta-adrenergic blockers or vasodilators may be present in the pharmaceutical compositions of the invention for use in the treatment of heart or vascular diseases or conditions. Similarly, for example, antihistamines, steroids (eg beclomethasone dipropionate, beclomethasone dip
ropionate), sodium cromoglycate, phosphodiesterase inhibitor or β-adrenergic stimulant,
Advantageously, it may be present in a pharmaceutical composition of the invention for use in treating a lung disease or condition.

[0074]

The invention is illustrated by the following non-limiting examples, unless otherwise stated: (i) Evaporation is carried out in a rotary evaporator in vacuum, the work-up method being filtration of residual solids. (Ii) operation at ambient temperature in the range of 18-25 ° C.,
(Iii) Column chromatography (by flash method) and medium pressure liquid chromatography (MPL).
C) is Merck of E. Merck, Darmstadt, W. Germany
Kieselgel silica (type 9385) or Merck Lic
Performed on reversed phase silica of hroprep RP-18 (type 9303); (iv) Yield is exemplary only and need not be the maximum to be achieved; (v) The final product of formula I is sufficient Microanalyzed and its structure was confirmed by nuclear magnetic resonance (NMR) and mass spectroscopy; using CDCl ₃ solution of the final product of formula I for the determination of NMR spectral data unless otherwise stated, The value of chemical shift is measured by Deltascalar,
The following abbreviations were used: s, singlet; d, doublet; t,
Triplet; m, multiplet; (vi) intermediates are generally not fully characterized,
And purity by thin layer chromatography, infrared (IR)
Or determined by NMR analysis; (vii) Melting point not accurate, Mettler SP62
Determined using automatic melting point or oil bath equipment; Formula I
The melting point of the final product of, for example, ethanol, methanol, ether or hexane was determined after crystallization from common organic solvents alone or in mixed form; and (viii) the following abbreviations were used: NMP N-methylpyrrolidin-2-one THF tetrahydrofuran DMF N, N-dimethylformamide Example 1 6-mercapto-1-methyl-1,2,3,4-tetrahydroquinolin-2-one (0.166 g) was added to 4- ( Two
-Chlorothiazol-5-yl) -4-methoxytetrahydropyran (0.2 g), potassium carbonate (0.13
g) and NMP (2 ml). The mixture was stirred and heated to 100 ° C. for 3 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO _4), and evaporated. The residue was purified by column chromatography using petroleum ether (bp 40-60 ° C) and a 1: 1 mixture of ethyl acetate as eluent. There was thus obtained 4-methoxy-4- [2- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio) thiazol-5-yl] tetrahydropyran (0.25 g). Melting point 114-115 ° C. (recrystallized from ethanol); NMR spectrum 1.97-2.01 (m, 4H),
2.69 (m, 2H), 2.94 (m, 2H), 3.0
5 (s, 3H), 3.38 (s, 3H), 3.7-3.
8 (m, 4H), 7.02-7.04 (d, 1H),
7.45 (s, 1H), 7.46-7.47 (d, 1
H), 7.55-7.85 (m, 1H).

The 6-mercapto-1-methyl-1,2,3,4-tetrahydroquinolin-2-one used as starting material was obtained as follows: concentrated hydrochloric acid (5 drops) and water (50 ml). ) Was added to di- (1-methyl-2-
Oxo-1,2,3,4-tetrahydroquinoline-6-
Ill) disulfide (European patent application no.
No. 2, specification 7; 38.4 g), triphenylphosphine (29 g) and 1,4-dioxane (300 m).
l) was added to the stirred mixture. The mixture was stirred at ambient temperature for 30 minutes. The mixture was concentrated by evaporation until the volume was reduced to about half. The residue was partitioned between ethyl acetate and 0.5N aqueous sodium hydroxide solution.
The aqueous phase was washed with diethyl ether and then acidified to pH 2 by adding dilute hydrochloric acid. The acidic mixture was extracted with ethyl acetate. Dry the organic phase (MgS
O ₄ ) and evaporated. The residual oil was dissolved in diethyl ether and hexane was added. Thus, 6-
Mercapto-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was obtained as a solid (35.5 g, 92%), which was used without further purification.

The 4- (2-chlorothiazol-5-yl) -4-methoxytetrahydropyran used as starting material was obtained as follows: sodium nitrite (6.
9 g) of saturated aqueous solution was added to concentrated hydrochloric acid (50 m
2-Aminothiazole (10 g) in 1) was added dropwise to a stirred solution. The mixture was stirred for 75 minutes at 0 ° C. Copper (I) chloride (9.9 g) was added dropwise, the reaction temperature was kept at 0 ° C. and the mixture was stirred for 2.5 hours. The mixture was neutralized by adding 10N aqueous sodium hydroxide solution. The mixture was partitioned between diethyl ether and water. The organic phase was washed with brine, dried (MgSO ₄₎
And evaporated. The residue was purified by distillation. Thus, 2-chlorothiazole (3.95 g, mercury 68 mm, boiling point 68 ° C.) was obtained.

A solution of 2-chlorothiazole (0.5 g) in diethyl ether (4 ml) and n-butyllithium (2.5 M in hexane, 1.8 ml) were added simultaneously.
Add to diethyl ether (5 ml) cooled to -78 ° C. The mixture was stirred and warmed to -20 ° C. A solution of tetrahydropyran-4-one (0.42g) in diethyl ether (5ml) was added dropwise. The mixture was stirred for 1 hour, warmed to 0 ° C. and then to ambient temperature. The mixture was partitioned between diethyl ether and saturated aqueous ammonium chloride solution. The organic phase was washed with brine, dried (MgSO _4), and evaporated. The residue was purified by column chromatography using petroleum ether (bp 40-60 ° C) and a 1: 1 mixture of ethyl acetate as eluent. Thus, 4- (2-chlorothiazole-5
-Yl) -4-hydroxytetrahydropyran (0.2
5g, 27%), mp 94 ° C.

Sodium hydride [0.045 g (obtained by removal of mineral oil dispersant)] was added to THF (1.5 m).
4- (2-chlorothiazol-5-yl) -4 in l)
-Hydroxytetrahydropyran (0.2g) was added and the mixture was stirred at ambient temperature for 1 hour. Methyl iodide (0.17 ml) was added and the mixture was stirred at ambient temperature for 12 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and brine. The organic phase was dried (MgSO _4), and evaporated. This residue
Purified by column chromatography using a 1: 1 mixture of petroleum ether (bp 40-60 ° C) and ethyl acetate as eluent. There was thus obtained 4- (2-chlorothiazol-5-yl) -4-methoxytetrahydropyran (0.2 g, 94%) as an oil.

Example 2 3-Chloroperoxybenzoic acid (0.141 g) was treated with 4-methoxy-4- [2 in methylene chloride (1.5 ml).
-(1-Methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio) thiazol-5-yl] tetrahydropyran (0.08 g) was added to a stirred solution. The mixture was stirred at ambient temperature for 5 hours. Saturated sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic phase is washed with brine and dried (Mg
SO ₄ ) and evaporated. Thus, 4-methoxy-
4- [2- (1-methyl-2-oxo-1,2,3,4
-Tetrahydroquinolin-6-ylsulfonyl) thiazol-5-yl] tetrahydropyran (0.071
g), melting point 163-164 ° C (recrystallized from ethanol)
was gotten.

NMR spectrum 2.03 to 2.05
(M, 4H), 2.70 (m, 2H), 3.0 (m, 2)
H), 3.1 (s, 3H), 3.78-3.81 (m,
4H), 7.12 (d, 1H), 7.73 (s, 1
H), 7.9 (m, 1H), 7.98-8.01 (m,
1H).

Example 3 Using a method similar to that described in Example 1, 6-mercapto-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was converted to (2S, 4R) -4- ( Reacted with 2-chlorothiazol-5-yl) -4-methoxy-2-methyltetrahydropyran to give (2S, 4R) -4-methoxy-2-methyl-4- [2- (1-methyl-2- Oxo-1,2,3,4-tetrahydroquinolin-6-ylthio) thiazol-5-yl] tetrahydropyran was obtained as a foam in 95% yield.

NMR spectrum 1.16-1.18
(D, 3H), 1.54-1.57 (m, 1H), 1.
81-2.02 (m, 3H), 2.67-2.71.
(M, 2H), 2.92-2.96 (m, 2H), 3.
04 (s, 3H), 3.38 (s, 3H), 3.77-
3.82 (m, 3H), 7.02-7.04 (d, 1
H), 7.42 (s, 1H), 7.46 (m, 1H),
7.56 (m, 1H).

(2S, 4R)-used as starting material
4- (2-Chlorothiazol-5-yl) -4-methoxy-2-methyltetrahydropyran was obtained as follows: a solution of 2-chlorothiazol (0.5 g) in diethyl ether (4 ml) and n-Butyllithium (2.5 M in hexane, 1.8 ml) was simultaneously cooled with diethyl ether (5 m) at −78 ° C. for 10 minutes.
l). The mixture was stirred for 3.5 hours,-
Warmed to 20 ° C. The mixture was recooled to -78 ° C and (2S) -2-methyltetrahydropyran-4-one [European Patent Application No. 03] in diethyl ether (4 ml).
85662 (Example 20); 0.43 g] was added. The mixture was stirred and warmed to -10 ° C. 5
% Aqueous ammonium chloride solution was added and the mixture was extracted with diethyl ether. The organic phase was washed with brine, dried (MgSO _4), and evaporated. The residue was purified by column chromatography using a 1: 1 mixture of petroleum ether (bp 40-60 ° C) and ethyl acetate as eluent. Thus (2S, 4R) -4- (2-chlorothiazol-5-yl) -4-hydroxy-2-methyltetrahydropyran (0.11 g, 13%) was obtained as an oil.

Sodium hydride (0.127 g, 5.2
7 mmol) was added to a solution of 4-hydroxy-2-methyltetrahydropyran thus obtained in THF (2.5 ml) and the mixture was stirred at ambient temperature for 1 hour. The mixture was cooled to 0 ° C. and methyl iodide (0.3
3 ml) was added. The mixture was stirred at ambient temperature for 2.5 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and brine. Dry the organic phase (Mg
SO ₄ ) and evaporated. The residue was purified by column chromatography using petroleum ether (bp 40-60 ° C) and a 1: 1 mixture of ethyl acetate as eluent. There was thus obtained (2S, 4R) -4- (2-chlorothiazol-5-yl) -4-methoxy-2-methyl-tetrahydropyran (0.268 g, 71%) as an oil, which was left standing. When it crystallized.

Example 4 Using a method similar to that described in Example 2, (2S, 4R)
Oxidize 4--4-methoxy-2-methyl-4- [2- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio) thiazol-5-yl] tetrahydropyran, (2S, 4R) -4-methoxy-2
-Methyl-4- [2- (1-methyl-2-oxo-1,
2,3,4-Tetrahydroquinolin-6-ylsulfonyl) thiazol-5-yl] tetrahydropyran was obtained as a foam with a yield of 98%. NMR spectrum 1.
18-1.20 (d, 3H), 1.61-1.65
(M, 1H), 1.942-2.10 (m, 3H), 2.
68-2.72 (m, 2H), 2.98-3.02
(M, 2H), 3.09 (s, 3H), 3.38 (s,
3H), 3.81-3.87 (m, 3H), 7.11-
7.13 (d, 1H), 7.71 (s, 1H), 7.8
9-7.90 (m, 1H), 7.98-8.01 (m,
1H).

Example 5 Potassium carbonate (15.5 g) was added to a solution of 6-mercapto-1-methyl-1,2,3,4-tetrahydroquinolin-2-one (19.7 g) in NMP (140 ml). The mixture was then stirred at ambient temperature for 10 minutes. (2
S, 4R) -4- (2-chlorothiazol-5-yl)
-4-Methoxy-2-methyltetrahydropyran (2
5.2 g) was added, the mixture was stirred and stirred for 1 hour over 2 hours.
Heated to 00 ° C. The mixture was cooled to ambient temperature and partitioned between diethyl ether and water. The organic phase was washed with water and brine, dried (MgSO _4), and evaporated. The residue was triturated under diethyl ether to give a crystalline solid. Thus (2S, 4R) -4-methoxy-
2-methyl-4- [2- (1-methyl-2-oxo-
1,2,3,4-Tetrahydroquinolin-6-ylthio) -thiazol-5-yl] tetrahydropyran (3
7.5 g, 91%), mp 78-79 ° C (recrystallized from diethyl ether).

(2S, 4R)-used as starting material
4- (2-chlorothiazol-5-yl) -4-methoxy-2-methyl-tetrahydropyran was obtained as follows: n-butyllithium (2.5M in hexane, 5
7.5 ml) was cooled to -78 ° C in THF (180 m).
A solution of diisopropylamine (19.3 ml) in 1) was added dropwise over 30 minutes. The mixture was stirred at -78 ° C for 1 hour. The reaction vessel was blocked from light and 2-chlorothiazole (15.0 g) was added dropwise over 20 minutes while the temperature of the reaction mixture was kept below -70 ° C. The mixture was stirred at -78 ° C for 1.5 hours.
(2S) -2-Methyltetrahydropyran-4-one (12.9 g) was added over 20 minutes. The mixture was stirred and briefly warmed to -25 ° C to give a homogeneous solution. The mixture is recooled to -70 ° C and at this temperature 1
Stir for hours. A 5% aqueous ammonium chloride solution was added and the mixture was extracted with diethyl ether. The organic solution was washed with brine, dried (MgSO _4), and evaporated. Thus, a mixture of (2S, 4R) -4- (2-chlorothiazol-5-yl) -4-hydroxy-2-methyltetrahydropyran and the corresponding (2S, 4S) isomer (29.4 g) is 1: 2. Obtained in a ratio of 4. The mixture thus obtained was mixed with diethyl ether (250 m
1) and cooled at 0 ° C. Concentrated (25% v / v) sulfuric acid was added and the mixture was stirred,
Warmed to ambient temperature. The mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with ethyl acetate (750 ml) and neutralized to pH 3 by addition of sodium hydrogen carbonate. The organic phase was washed with brine, dried (MgSO ₄₎ and evaporated, (2S, 4R) -4- ( -5- 2- chlorothiazol-yl) -4-hydroxy-2-methyltetrahydropyran and correspondingly A mixture of (2S, 4S) isomers (26 g) was obtained in a ratio of 9: 1. This material was used as an eluent for petroleum ether (boiling point 40-60
C) and ethyl acetate and purified by column chromatography using a 1: 1 mixture. Thus, (2S, 4
R) -4- (2-chlorothiazol-5-yl) -4-
Hydroxy-2-methyltetrahydropyran (21 g,
79%) was obtained.

Sodium hydride (60% dispersion in mineral oil, 14.5 g, 0.36 mol) was (2S, 4R) -4- (2- in 2 ml of THF (150 ml) cooled to 0 ° C.
Chlorothiazol-5-yl) -4-hydroxy-2-
1 in a solution of methyltetrahydropyran (42.15g)
It was added in portions over 5 minutes. The mixture was stirred at 0 ° C for 45 minutes. Methyl iodide (22.5 ml) was added dropwise and the mixture was stirred and warmed to ambient temperature during 2 hours. The mixture was recooled to 0 ° C. and a solution of brine was added. The mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO _4), and evaporated. Petroleum ether (boiling point 40-60) with the residue as eluent
C) and 7: 3 mixture of ethyl acetate. Thus, (2
S, 4R) -4- (2-chlorothiazol-5-yl)
-4-Methoxy-2-methyltetrahydropyran (4
0.9g, 91%), mp 40-42 ° C.

Example 6 Using a method similar to that described in Example 1, but adding a catalytic amount of potassium iodide (0.01 g) and adding 6-mercapto-1-methyl-1,2,3,4-tetrahydro. The quinolin-2-one is reacted with 4- (2-chlorothiazol-5-yl) -4-methoxy-2,2-dimethyltetrahydropyran to give 4-methoxy-2,2-dimethyl-4.
-[2- (1-methyl-2-oxo-1,2,3,4-
Tetrahydroquinolin-6-ylthio) thiazol-5
-Yl] tetrahydropyran was obtained as a foam in a yield of 80%.

NMR spectrum 1.2 (s, 3H),
1.4 (s, 3H), 1.6-1.75 (m, 2H),
1.9-2.0 (m, 2H), 2.70 (m, 2H),
2.95 (m, 2H), 3.02 (s, 3H), 3.4
(S, 3H), 3.65 (m, 1H), 3.95 (m,
1H), 7.03 (m, 1H), 7.42 (s, 1
H), 7.46 (m, 1H), 7.55 (m, 1H).

The 4- (2-chlorothiazol-5-yl) -4-methoxy-2,2-dimethyltetrahydropyran used as starting material was obtained as follows: 2- in diethyl ether (8 ml). Chlorothiazole (0.
75 g) and n-butyllithium (1.4 M in hexane, 4.5 ml) at the same time, but separately,
Add to diethyl ether (8 ml) cooled to 80 ° C. The mixture was stirred at -75 ° C for 10 minutes, then-
Warmed to 30 ° C. Recool the mixture to -80 ° C,
A solution of 2,2-dimethyltetrahydropyran-4-one (0.76g) in diethyl ether (5ml) was added. The mixture was stirred and warmed to -30 ° C. The mixture was poured into a mixture of ice and saturated aqueous ammonium chloride solution. The organic solution is washed with brine and dried (Mg
SO ₄ ) and evaporated. The residue was purified by column chromatography using a 10: 3 mixture of hexane and ethyl acetate as eluent. Thus, 4-
(2-chlorothiazol-5-yl) -4-hydroxy-2,2-dimethyltetrahydropyran (0.67 g,
46%) was obtained as an oil.

NMR spectrum 1.2 (s, 3H),
1.45 (s, 3H), 1.8-2.15 (m, 4
H), 3.75 (m, 1H), 4.1 (m, 1H),
7.38 (s, 1H).

Using a method similar to that described in the last paragraph for the preparation of the starting material of Example 3, but using DMF in THF.
Was used as a reaction solvent instead of
Methylation of hydroxy-2,2-dimethyltetrahydropyran, 4- (2-chlorothiazol-5-yl)-
4-Methoxy-2,2-dimethyltetrahydropyran was obtained as an oil in a yield of 79%.

Example 7 Sodium hydride (60% dispersion in mineral oil, 0.06
g) was added to 4-hydroxy-2,6-dimethyl-4- [2- (1-methyl-) in DMF (2 ml) cooled to 0 ° C.
2-oxo-1,2,3,4-tetrahydroquinoline-
6-ylthio) thiazol-5-yl] tetrahydropyran (0.27 g) was added portionwise into a stirred solution.
The mixture was stirred at 0 ° C for 30 minutes. Methyl iodide (0.2 ml) was added. The mixture was warmed to ambient temperature and stirred for 16 hours. The mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic phase was washed with brine, dried (MgSO _4), and evaporated. The residue was purified by column chromatography using an increasing polar mixture of hexane and ethyl acetate as eluent. Thus 4-methoxy-2,6-dimethyl-
4- [2- (1-methyl-2-oxo-1,2,3,4
-Tetrahydroquinolin-6-ylthio) thiazole-
5-yl] tetrahydropyran (0.063 g) was obtained as a gum.

NMR spectrum 1.15 (d, 3H),
1.4 (d, 3H), 1.65 (m, 2H), 1.9-
2.1 (m, 2H), 2.70 (m, 2H), 2.95
(M, 2H), 3.05 (s, 3H), 3.37 (s,
3H), 4.1 (m, 2H), 7.03 (m, 1H),
7.40 (s, 1H), 7.47 (m, 1H), 7.5
5 (m, 1H).

4-hydroxy- used as starting material
2,6-Dimethyl-4- [2- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio) thiazol-5-yl] tetrahydropyran is obtained as follows: The procedure described in the first paragraph for the preparation of the starting material of Example 6 is repeated, but using 2,6-dimethyltetrahydropyran-4-one instead of 2,2-dimethyltetrahydropyran-4-one. did. Thus, 77% of 4- (2-chlorothiazol-5-yl) -4-hydroxy-2,6-dimethyltetrahydropyran is obtained.
It was obtained with a yield of.

NMR spectrum 1.2 (s, 3H),
1.5 (s, 3H), 1.7-2.0 (m, 3H),
2.16 (m, 2H), 4.2 (m, 2H), 7.38
(S, 1H).

6-mercapto-1-methyl-1,2,
3,4-tetrahydroquinolin-2-one (0.32
g), 4- (2-chlorothiazol-5-yl) -4-
A mixture of hydroxy-2,6-dimethyltetrahydropyran (0.3g), potassium carbonate (0.33g), potassium iodide (0.01g) and DMF (3ml) was stirred and heated to 100 ° C for 4 hours. . The mixture was cooled to ambient temperature and partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic solution was washed with brine, dried (MgSO _4), and evaporated. The residue was purified by column chromatography using an increasing polar mixture of hexane and ethyl acetate as eluent.
Thus 4-hydroxy-2,6-dimethyl-4- [2
-(1-Methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio) thiazol-5-yl] tetrahydropyran (0.26 g, 53%) was obtained as a foam.

NMR spectrum 1.2 (s, 3H),
1.5 (s, 3H), 1.7-1.9 (m, 3H),
2.15 (m, 1H), 2.66 (m, 1H), 2.9
5 (m, 2H), 3.39 (s, 3H), 4.18
(M, 2H), 7.0 (d, 1H), 7.5 (m, 2)
H), 7.55 (m, 1H).

Example 8 The procedure similar to that described in Example 1 is repeated except that triphenylphosphine (0.04 g) is added and 6-mercapto-1-methyl-1,2,3,4-tetrahydroquinoline-2 is added. -ON (0.153g), (2S, 4R) -4-
(5-Bromothiazol-2-yl) -4-methoxy-
Reacted with 2-methyl-tetrahydropyran (0.23 g) to give (2S, 4R) -4-methoxy-2-methyl-4.
-[5- (1-methyl-2-oxo-1,2,3,4-
Tetrahydroquinolin-6-ylthio) thiazole-2
-Yl] tetrahydropyran was obtained as a foam in a yield of 72%.

NMR spectrum 1.15 to 1.20
(D, 3H), 1.60 (m, 1H), 1.90-2.
05 (m, 3H), 2.65-2.75 (m, 2H),
2.90-3.00 (m, 2H), 3.05 (s, 3
H), 3.4 (s, 3H), 3.75-3.85 (m,
3H), 7.05 (d, 1H), 7.4 (s, 1H),
7.45 (m, 1H), 7.55 (m, 1H).

(2S, 4R)-used as starting material
4- (5-Bromothiazol-2-yl) -4-methoxy-2-methyl-tetrahydropyran was obtained as follows: 2,5-dibromothiazole (2 g, J. in diethyl ether (3 ml). Chem. Soc., Perkin Trans.
I, 1992, 215-219) was added dropwise to a solution of n-butyllithium (2.5M in hexanes, 3.7 ml) in diethyl ether (80 ml) cooled to -100 ° C. The mixture was stirred for 5 minutes and (2S) -2-methyltetrahydropyran-4-one (0.845g) was added while the temperature of the reaction mixture was kept at -100 ° C. The mixture was stirred for 45 minutes and quenched with a 5% aqueous solution of ammonium chloride. The mixture was extracted twice with diethyl ether, washed with brine, dried (MgSO _4), filtered and evaporated. The oil was purified by column chromatography using a 1: 1 mixture of petroleum ether and ethyl acetate as eluent. Thus, (2S, 4
A mixture of (S)-and (2S, 4R) -4- (5-bromothiazol-2-yl) -4-hydroxy-2-methyltetrahydropyran (1.177 g, 46%) was obtained as an oil.

The mixture (1 g) thus obtained was dissolved in diethyl ether (15 ml) and the solution was cooled to 0 ° C. Concentrated (30% v / v) sulfuric acid (10 ml) was added and the mixture was stirred and warmed to ambient temperature. The mixture was stirred at ambient temperature for 16 hours. The mixture was neutralized by adding sodium hydrogen carbonate, extracted 3 times with diethyl ether, washed with brine and dried (M.
gSO ₄ ), filtered and evaporated. The oil was purified by column chromatography using a 1: 1 mixture of petroleum ether and ethyl acetate as eluent.
Thus (2S, 4R) -4- (5-bromothiazol-2-yl) -4-hydroxy-2-methyltetrahydropyran was obtained as an oil (0.707 g, 70%).

Sodium hydride (60% dispersion in mineral oil, 0.045 g, 0.0018 mol) in (2S, 4R) -4 in THF (2.5 ml) cooled to 0 ° C.
Added to a solution of-(5-bromothiazol-2-yl) -4-hydroxy-2-methyltetrahydropyran (0.25g). The mixture was stirred at 0 ° C for 45 minutes.
Methyl iodide (0.13 ml) was added dropwise and the mixture was stirred and allowed to warm to ambient temperature during 2 hours. A solution of saline was added, the organic solution was extracted with ethyl acetate and dried (M
gSO ₄ ), filtered and evaporated. The oil was purified by column chromatography using a 1: 2 mixture of petroleum ether and ethyl acetate as eluent. Thus (2S, 4R) -4- (5-bromothiazole-2-
Yl) -4-Methoxy-2-methyltetrahydropyran was obtained as an oil (0.233 g, 89%).

Example 9 A representative pharmaceutical preparation containing a compound of formula I or a pharmaceutically acceptable salt thereof (hereinafter compound X) for use therapeutically or prophylactically in humans (A) Tablet I mg / tablet Compound X 100 Lactose Ph. Eur. 182.75 Croscarmellose sodium 12.0 Corn starch paste (5% w / v paste) 2.25 Magnesium stearate 3.0 (b) Tablet II mg / tablet Compound X 50 Lactose Ph. Eur. 223.75 Croscarmellose sodium 6.0 Corn starch 15.0 Polyvinylpyrrolidone (5% w / v paste) 2.25 Magnesium stearate 3.0 (c) Tablet III mg / tablet Compound X 1.0 Lactose Ph. Eur 93.25 Croscarmellose sodium 4.0 Corn starch paste (5% w / v paste) 0.75 Magnesium stearate 1.0 (d) Capsules mg / capsule Compound X 10 Lactose Ph. Eur. 488.5 Magnesium stearate 1.5 (e) Injection I (50 mg / ml) Compound X 5.0% w / v 1M sodium hydroxide solution 15.0% v / v 0.1M hydrochloric acid (to pH 7.6) Adjustment) Polyethylene glycol 400 4.5% w / v Water for injection Up to 100% (f) Injection II (10 mg / ml) Compound X 1.0% w / v Sodium phosphate BP 3.6% w / v 0. 1M sodium hydroxide solution 15.0% w / v Water for injection Up to 100% (g) Injection III (1 mg / ml, buffered to pH 6) Compound X 0.1% w / v Sodium phosphate BP 2.26% w / V Citric acid 0.38% w / v Polyethylene glycol 400 3.5% w / v Water for injection Up to 100% (h) Aerosol I mg / ml Compound X 10.0 Sorbitan triolea 13.5 trichlorofluoromethane 910.0 dichlorodifluoromethane 490.0 (i) Aerosol II mg / ml Compound X 0.2 sorbitan trioleate 0.27 trichlorofluoromethane 70.0 dichlorodifluoromethane 280.0 dichlorotetra Fluoroethane 1094.0 (j) Aerosol III mg / ml Compound X 2.5 Sorbitan trioleate 3.38 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0 Dichlorotetrafluoroethane 191.6 (k) Aerosol IV mg / ml ml Compound X 2.5 Soybean lecithin 2.7 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0 Dichlorotetrafluoroethane 191.6 Note: The above preparation is a preparation. It can be obtained by a conventional method known in the scientific field. Tablets (a)-(c)
Can be enteric coated by conventional methods, eg by coating with cellulose acetate phthalate. The aerosol preparations (h)-(k) can also be used in connection with standard metered dose aerosol despacers, the suspending agents sorbitan trioleate and soybean lecithin being used in combination with other suspending agents such as sorbitan monooleate. It can be replaced by art, sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleic acid.

Claims (12)

[Claims] 1. Formula I: [In the formula, Q represents 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl or 2-oxo-1,2-dihydroquinolin-6-yl, which are attached to the nitrogen atom at the 1-position. has a C ₁ -C ₄ alkyl substituents, X ¹ represents thio, sulphinyl or sulphonyl, Ar represents thiazolediyl, R ¹ is C ₁ -C ₄ alkyl, C ₃ -C
₄ alkenyl or C ₃ -C ₄ alkynyl, and R ² and R ^{3 taken} together are of the formula: —A ² —X ² —A ³ —
Represents a ring having 5 or 6 membered ring atoms together with the carbon atom to which A ² and A ³ are attached, wherein A ² and A ³ are the same or different. Or each represents C ₁ -C ₃ alkylene, X ² represents oxy, and the ring has 1 or 2 C ₁ -C ₄ alkyl substituents] Tolerable salt. 2. Q is 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl or 2-oxo-1,2.
- represents dihydro-6-yl, which has a C ₁ -C ₄ alkyl substituents on the nitrogen atom at the 1-position, X ¹ represents thio, sulphinyl or sulphonyl, Ar is 2,5-thiazol Represents a diyl (bonded to the X ¹ group at the 2-position), R ¹ represents C ₁ -C ₄ alkyl, C ₃ -C ₄ alkenyl or C ₃ -C ₄ alkynyl, R ² and R ³ are taken together, formula: -A ² -X ² -A ³ - group and the formation of the group a ²
And A ³ together with the carbon atom to which they are attached represent a ring having a 5- or 6-membered ring atom, wherein A ² and A ³ may be the same or different and each is C ₁ -C ₃ alkylene. Wherein X ² represents oxy, the ring having one or two C ₁ -C ₄ alkyl substituents] and the thiazole derivative of formula I according to claim 1 or a pharmaceutically acceptable salt thereof. Sex salt. 3. Q is 1-methyl-2-oxo-1,2,
Represents 3,4-tetrahydroquinolin-6-yl, X ¹
Represents thio or sulfonyl, Ar represents 2,5-thiazoldiyl (bonded to the X ¹ group at the 2-position), R ¹ represents methyl, and R ² and R ³ together represent the formula: A
^2— X ² —A ³ — forms a group which, together with the carbon atom to which A ² and A ³ are attached, represents a ring having a 6-membered ring atom, wherein A ² and A 3 Each of ³ represents ethylene, X ² represents oxy, which ring may have a methyl substituent in the α-position to X ² ] or a thiazole derivative of formula I according to claim 1 A pharmaceutically acceptable salt. 4. Q is 1-methyl-2-oxo-1,2,
Represents 3,4-tetrahydroquinolin-6-yl, X ¹
Represents thio or sulfonyl, Ar represents 2,5-thiazoldiyl (bonded to the X ¹ group at the 2-position), R ¹ represents methyl, and R ² and R ³ together represent the formula: C
H ₂ CH ₂ OCH (CH ₃ ) CH ₂ —] and the thiazole derivative of formula I according to claim 1 or a pharmaceutically acceptable salt thereof. 5. (2S, 4R) -4-methoxy-2-methyl-4- [2- (1-methyl-2-oxo-1,2,2
3. The thiazole derivative of formula I or a pharmaceutically acceptable salt thereof according to claim 1, which is 3,4-tetrahydroquinolin-6-ylthio) thiazol-5-yl] tetrahydropyran. 6. A process for producing a thiazole derivative of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the compound of formula: Q-X ¹ -H is Formula II: Where a pharmaceutically acceptable salt of a compound of formula I is required by coupling with a compound of the formula: Z represents a removable group, said compound is suitable in a conventional manner. When an optically active form of a compound of formula I is required, which is reacted with a suitable acid or base, the above method is carried out with an optically active starting material, or the racemate of said compound is obtained by conventional methods. A method for producing a thiazole derivative or a pharmaceutically acceptable salt thereof, which is characterized in that 7. A process for producing a thiazole derivative of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the formula: Q-Z [wherein Z is Representing a releasable group] is represented by the formula III: When an optically active form of a compound of formula I is required by coupling with a compound of formula I, the process described above is carried out with an optically active starting material, or the racemate of said compound is prepared by conventional methods. A method for producing a thiazole derivative or a pharmaceutically acceptable salt thereof, which is characterized in that 8. A process for producing a thiazole derivative of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the formula: Q-X ¹ -Z [wherein Z
Represents a releasable group, or when X ¹ is a thio group, Z may represent the formula: Q—X ¹ —], a compound of formula IV: [Wherein M represents an alkali metal or an alkaline earth metal, or M represents a magnesium halide moiety of a conventional Grignard reagent], and the optically active form of the compound of formula I is coupled with the organometallic reagent. When necessary, the above method is carried out using an optically active starting material, or a racemate of the above compound is resolved by a conventional method. Process for the preparation of a salt that is physiologically acceptable. 9. A process for the preparation of a thiazole derivative of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, which comprises the formula V: Alkylation of the compound represented by the formula with a compound represented by the formula: R ¹ -Z [wherein Z represents a releasable group], and when an optically active form of the compound of the formula I is required, Process for carrying out the process with optically active starting materials, or resolving racemates of the above compounds using conventional processes for the preparation of thiazole derivatives or their pharmaceutically acceptable salts . 10. A process for the preparation of a compound of formula I wherein Q has an alkyl substituent on the available nitrogen atom, wherein a compound of formula I wherein Q has a hydrogen atom on the available nitrogen atom is alkylated to form a compound of formula I When an optically active form is required, the above method is carried out using an optically active starting material, or a racemate of the above compound is resolved by a conventional method. A method for producing a pharmaceutically acceptable salt thereof. 11. X ¹ is in the preparation of compounds of formula I representative of the sulfinyl group or a sulfonyl group, oxidizing the compound of formula I in which X ¹ represents thio group, are required optically active form of a compound of the formula I In some cases, the above method is carried out using an optically active starting material, or the racemate of the above compound is resolved using conventional methods, or a thiazole derivative or a pharmaceutically acceptable preparation thereof. Method for the production of organic salts. 12. A thiazole derivative of the formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in combination with a pharmaceutically acceptable diluent or carrier. A pharmaceutical composition for use in diseases or conditions mediated by leukotrienes contained therein.