JPH0725756A - Chemotaxis-inhibiting agent composed of aryloxypropanolamine - Google Patents

Abstract

PURPOSE:To obtain the inhibiting agent containing an amine derivative expressed by a specific structural formula, having action to inhibit the chemotaxis induced by a monocyte chemotactic factor and useful for the treatment and prevention of arteriosclerosis, etc. CONSTITUTION:This inhibiting agent contains an aryloxypropanolamine derivative of the formula [R1 is branched lower alkyl, preferably isopropyl; R2 is H, halogen, 1-4C alkyl, etc.; R3 is H or 1-4C alkyl; preferably R2 and R3 together form unsubstituted 6C unsaturated carbon ring; R4 is H, (substituted) 1-4C alkyl, etc.; R5 is H, halogen, etc.] and its pharmacologically allowable acid addition salt as an active component.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The present invention relates to the onset, progress and maintenance of pathological conditions such as infiltration of blood monosites into tissues such as arteriosclerosis, rheumatoid arthritis, osteoarthritis, diabetic retinopathy and pulmonary fibrosis. The present invention relates to a cell migration inhibitor useful as a therapeutic and / or preventive agent for diseases that play an important role in

[0002]

2. Description of the Related Art Monosite migration factor MCP-1 / MCA
F is a cell-specific chemotactic factor produced by T lymphocytes, macrophages, smooth muscle cells, fibroblasts, vascular endothelial cells, etc. (reference: Leonard, EJ
And Yoshimura, T. (1990) Immunology Today 1st
1, 97-101, etc.), and overexpression is observed in human and animal arteriosclerotic lesions or lesions of rheumatoid arthritis patients (Reference: Nelken, NA et al. (1991)).
Journal of Clinical Investigation, Vol. 88, 1121-1127, Koch, AE et al. (19
92) Journal of Clinical Investigation, Vol. 90, p. 772-779, etc.). That is,
Overexpression of such a monosite migration factor MCP-1 / MCAF causes infiltration of monosites into lesions such as arteriosclerotic lesions, resulting in the onset and progression of diseases such as arteriosclerosis and rheumatoid arthritis. It is believed to be deeply involved in maintenance. Therefore, the monosite migration factor MCP-1 / MCA
Drugs that inhibit cell migration caused by F are:
It is expected to be useful as a therapeutic agent and / or preventive agent for arteriosclerosis, rheumatoid arthritis, etc., but until now, no such inhibitor has been reported.

On the other hand, aryloxypropanolamine derivatives are known to block β-Adrenergic receptor (Reference: Annual Report of Medicinal Che).
mistry Vol. 14, p. 81 (1979), New York Acade
mic Press, etc.) is a monosite migration factor MCP-1 /
It is not yet known to inhibit cell migration caused by MCAF.

[0004]

In view of such conventional techniques, the present inventors have found that the monosite migration factor MCP-1 /
As a result of intensive research to find a drug that inhibits the cell migration caused by MCAF, the aryloxypropanolamine derivative or a pharmaceutically acceptable salt thereof is found to cause cell migration caused by the monosite migration factor MCP-1 / MCAF. Excellent activity, which inhibits
The inventors have also completed the present invention by finding that they have an excellent activity of inhibiting the binding of the monocytic migration factor MCP-1 / MCAF to target cells.

[0005]

That is, the present invention provides the following formula [I]:

[0006]

[Chemical 2]

[Where R₁Is C₃~ C_FourBranched lower
Represents an alkyl group; R₂Is hydrogen atom, halogen atom, C
₁~ C_FourLower alkyl group, C₁~ C_FourLower alkoxy
Base, C₃~ C_FiveLower cycloalkyl group, C₂~ C_FourLow grade
Alkenyl group, C₂~ C_FourLower alkenyloxy group, C
₂~ C_FourLower alkynyloxy group, C₂~ C_FiveLower reed
Represents a chloro group or a cyano group; R₃Is a hydrogen atom, or
C₁~ C_FourRepresents a lower alkyl group; R_FourIs a hydrogen atom, nothing
Substituted or substituted C₁~ C_FourLower alkyl group, none
Substituted or substituted C₁~ C_FourLower alkoxy group,
Halogen atom, C₂~ C_FiveLower acylamino group, C₂~
C_FiveLower acyloxy group, hydroxyl group, C_Four~ C ₇Low grade
Roalkyl urea group, or C₃~ C₇Lower dialkyl urine
Represents a group; R_FiveIs a hydrogen atom, a halogen atom, or C
₁~ C_FourRepresents a lower alkyl group; or R₂And R₃
Together with unsubstituted or substituted C_Five~ C₆of
May form a saturated or unsaturated carbocycle, or R
₂And R₃Replaced together or not
In addition, a 5-membered ring containing oxygen or nitrogen atoms in the ring
An incense ring may be formed. ] Aryl oxyp represented by
Lopanolamine derivatives and their pharmaceutically acceptable
A cell migration inhibitor containing an acid adduct as an active ingredient.
It

In the above formula [I], R ₁ represents a C ₃ -C ₄ branched lower alkyl group. Preferable specific examples thereof include isopropyl, sec-butyl and tert-butyl groups. Of these, an isopropyl group is preferable.

R in the formula [I]₂Is a hydrogen atom, halogen
Atom, C₁~ C_FourLower alkyl group, C₁~ C_FourLow rank
Lucoxy group, C₃~ C_FiveLower cycloalkyl group, C₂~
C_FourLower alkenyl group, C₂~ C_FourLower alkenyl oki
Shi group, C₂~ C_FourLower alkynyloxy group, C₂~ C_Five
It represents a lower acyl group or a cyano group. With a halogen atom
Fluorine atom, chlorine atom, bromine atom, iodine atom
And so on. A preferred specific example is a chlorine atom.
Is mentioned. C₁~ C_FourThe lower alkyl group is, for example,
Methyl, ethyl, n-propyl, isopropyl, n-bu
Chill, sec-butyl, t-butyl, isobutyl group, etc.
C₁~ C_FourMeans a linear or branched alkyl group of
Preferable specific examples thereof include methyl and isopropyl groups.
Is mentioned. C₁~ C_FourThe lower alkoxy group means the above
C₁~ C_FourA group consisting of a lower alkyl group and an oxy group is meant.
A methoxy group is mentioned as a preferable specific example for taste.
C ₃~ C_FiveA lower cycloalkyl group is C₃~ C_FiveRing of
Means an alkyl group of the form
Examples thereof include cyclopropyl and cyclopentyl. C
₂~ C_FourThe lower alkenyl group is, for example, ethynyl or ari.
C such as benzyl, propenyl and butenyl groups₂~ C_FourThe straight chain of
Means a branched alkenyl group, and preferable examples thereof
Examples thereof include an allyl group. C₂~ C_FourLower Al
The alkenyloxy group is the above C₂~ C_FourWith a lower alkenyl group
It means a group consisting of an oxy group, and preferable specific examples include:
An allyloxy group etc. are mentioned. C₂~ C_FourLower Al
A quinyloxy group is C₂~ C_FourLower alkynyl group
A group consisting of a xy group and a preferable specific example thereof.
Is, for example, a propargyloxy group. C₂~ C_Five
The lower acyl group means the above lower alkyl group and carbonyl group.
And a group consisting of
Examples include cetyl group and isopropylcarbonyl group.
It

R ₃ in the formula [I] represents a hydrogen atom or a C ₁ -C ₄ lower alkyl group. The C ₁ -C ₄ lower alkyl group has the same definition as the above R ₂ , and a preferable specific example thereof is a methyl group.

R ₄ in the formula [I] is a hydrogen atom, an unsubstituted or substituted C ₁ -C ₄ lower alkyl group, an unsubstituted or substituted C ₁ -C ₄ lower alkoxy group, a halogen atom, C ₂ To C ₅ lower acylamino group, C _{2 to} C
_{5 represents a} lower acyloxy group, a hydroxyl group, a C ₄ -C ₇ lower cycloalkylurea group, or a C ₃ -C ₇ lower dialkylurea group.

The definition of C ₁ -C ₄ lower alkyl group, C ₁ -C ₄ lower alkoxy group, and halogen atom is the same as the definition of R ₂ mentioned above. The C ₂ -C ₅ lower acylamino group means a group consisting of the C ₂ -C ₅ lower acyl group and the amino group described in the definition of R ₂ , and a preferable specific example thereof is an ethylcarbonylamino group. , Acetylamino group,
Examples include propylcarbonylamino group.

The term "C ₂ -C ₅ lower acyloxy group" means a group consisting of the C ₂ -C ₅ lower acyl group and the oxy group mentioned in the definition of R ₂ , and a preferable specific example thereof is acetyl. An oxy group etc. are mentioned.

The C ₄ -C ₇ lower cycloalkylurea group means a group consisting of a C ₃ -C ₆ lower cycloalkyl group and a urea group, and a preferable specific example thereof is a 3-cyclohexylurea group. And so on. The C ₃ -C ₇ lower dialkylurea group means a group consisting of a C ₁ -C ₃ linear or branched alkyl group and a urea group, and a preferable example thereof is a 3,3-diethylurea group. And so on.

The C ₁ -C ₄ lower alkyl group and the C ₁ -C ₄ lower alkoxy group may be further substituted, and in this case, the substituent is a carbamoyl group, a substituted or unsubstituted C group. ₁ -C ₄ lower alkoxy groups, C ₂ -C ₅ lower alkyl urea groups or C ₂ -C _5,
A lower alkyloxycarbonylamino group may be mentioned.
Preferable specific examples of the substituted C ₁ -C ₄ lower alkyl group include carbamoylmethyl group, methoxyethyl group, cyclopropylmethoxyethyl group, isopropoxyethoxymethyl group, 3-isopropylureaethyl group, methoxycarbonylamino group. Examples thereof include an ethyl group. Preferable specific examples of substituted C ₂ -C ₅ lower alkoxy group, a cyclopropyl methoxyethoxy group, and a methoxyethoxy group.

R ₅ in the formula [I] represents a hydrogen atom, a halogen atom or a C ₁ -C ₄ lower alkyl group. The halogen atom and the C ₁ -C ₄ lower alkyl group are the same as defined for R ₂ . Preferable specific examples thereof include a chlorine atom and a methyl group.

R ₂ and R ₃ in formula [I] may together form an unsubstituted or substituted C ₅ -C ₆ saturated or unsaturated carbocycle. Examples of the substituent on the carbocycle in this case include a hydroxyl group. Preferable specific examples of the ring portion of the compound represented by the formula [I] obtained in that case include structures represented by the following formulas [II] and [III].

[0018]

[Chemical 3]

When R ₂ and R ₃ in the formula [I] together form a C ₆ unsaturated carbocycle, they may form a carboaromatic ring. Specific preferred examples of the ring portion of the compound represented by the formula [I] obtained in this case include the structure of the following formula [IV].

[0020]

[Chemical 4]

R ₂ and R ₃ in the formula [I] may be taken together to form a 5-membered aromatic ring containing an oxygen atom or a nitrogen atom in the unsubstituted or substituted ring. In this case, the substituents are C ₁ -C ₄ lower alkyl group, C ₂ -C
₅ Lower acyl group, cyano group and the like can be mentioned. Preferable specific examples of the ring moiety of the compound represented by the formula [I] obtained in this case include the following formulas [V] [VI] and [VI].
The structure represented by [I] is mentioned.

[0022]

[Chemical 5]

The aryloxypropanolamine derivative in the present invention may be an acid adduct, and examples of such an acid include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, citric acid and malic acid. , Tartaric acid, fumaric acid,
Organic acids such as methanesulfonic acid may be mentioned.

The aryloxypropanolamine derivative in the present invention includes a racemate and all possible optically active forms.

According to the present invention, the following compounds may be mentioned as preferred specific examples of the aryloxypropanolamine derivative represented by the above formula [I].

[0026]

[Chemical 6]

The aryloxypropanolamine derivative of the present invention represented by the above formula [I] is a conventionally known compound, for example, CH469002, DE20077.
No. 51, US3337628, US35
20919, US3857952, U
It can be obtained by the method described in the specification of S3408387, GB1077703 or the like.

The therapeutically effective amount of the aryloxypropanolamine derivative represented by the above formula [I] of the present invention or a pharmaceutically acceptable acid adduct thereof is a pharmaceutically acceptable carrier and / or a diluent. The cell migration inhibitor of the present invention can be obtained by forming a pharmaceutical composition or the like together with the agent.

That is, the aryloxypropanolamine derivative of the present invention and its pharmaceutically acceptable acid adduct are administered orally or parenterally such as intravenously, subcutaneously, intramuscularly, transdermally, and rectally. be able to.

Examples of the dosage form for oral administration include tablets, pills, granules, powders, solutions, suspensions and capsules.

In the form of tablets, for example, excipients such as lactose, starch and crystalline cellulose; binders such as carboxymethyl cellulose, methyl cellulose and polyvinylpyrrolidone; disintegrants such as sodium alginate, sodium hydrogen carbonate and sodium lauryl sulfate. And the like can be used for molding by an ordinary method.

Pills, powders and granules can also be formed by the usual method using the above-mentioned excipients and the like.
Liquids and suspensions are formed by a usual method using, for example, glycerin esters such as tricaprylin and triacetin, alcohols such as ethanol and the like. Capsules are formed by filling granules, powders or liquids into capsules such as gelatin.

The subcutaneous, intramuscular, and intravenous administration forms include injections in the form of aqueous or non-aqueous solutions. As the aqueous solution, for example, physiological saline is used. As the non-aqueous solution, for example, propylene glycol, polyethylene glycol, olive oil, ethyl oleate, etc. are used, and if necessary, a preservative, a stabilizer and the like are added. The injection is sterilized by appropriately performing treatments such as filtration through a bacteria-retaining filter and addition of a germicide.

As the dosage form for transdermal administration, for example, ointment,
Creams and the like can be mentioned. Ointments are oils and fats such as castor oil and olive oil; vaseline and the like are used, creams are fatty oils, and emulsifiers such as diethylene glycol and sorbitan monofatty acid ester are used, and they are molded by a usual method. It

For rectal administration, usual suppositories such as gelatin soft capsules are used.

The dose of the aryloxypropanolamine derivative of the present invention or a pharmaceutically acceptable acid adduct thereof varies depending on the type of disease, administration route, age of patient, sex, degree of disease, etc. 1 to 1
It is 500 mg / day.

[0037]

INDUSTRIAL APPLICABILITY The cell migration inhibitor comprising the aryloxypropanolamine derivative of the present invention or a pharmaceutically acceptable acid adduct thereof is a monosite migration factor MC.
Diseases that have the effect of inhibiting cell migration caused by P-1 / MCAF, and therefore infiltration of blood monosite into tissues plays an important role in the onset, progression, and maintenance of pathological conditions, such as arteriosclerosis It is useful as a therapeutic and / or prophylactic drug for rheumatoid arthritis, osteoarthritis, diabetic retinopathy, pulmonary fibrosis and the like.

[0038]

EXAMPLES The present invention will be described in more detail below with reference to examples.

[0039]

Example 1 Measurement of Cell Migration Inhibitory Activity For the purpose of investigating the cell migration inhibition activity of the test compounds shown in Table 1, the measurement of cell migration caused by the monosite migration factor MCP-1 / MCAF was derived from human promonocytes. Using leukemia cells THP-1 as migratory cells, the method of Fall et al. (J. Immunol. Methods. 33 , 239-247 (198
According to 0), it carried out as follows. That is, 96-well micro chemotaxis chamber (Neuroprobe; registered trademark)
2 × 10 ⁶ / ml (RPMI 1640 (Flow Laborat) was placed in the upper chamber (200 μl) of the chamber.
Humans Recombinant MCP-with the same solution in the lower chamber (35 μl)
1 (manufactured by Peprotech) diluted to a final concentration of 20 ng / ml was added, and a polycarbonate filter (PVP-free, Neuroprobe; registered trademark) was placed between both chambers.
Were fixed and incubated at 37 ° C. under 5% CO ₂ for 2 hours. Take out the filter, DiffQuic
The cells that had migrated to the lower surface of the filter were fixed and stained with solution k (manufactured by International Reagents Co., Ltd.), and then a plate reader (Molecular
(Manufactured by Device Co.) and measured at a measurement wavelength of 550 nm to obtain an average value of 3 wells, which was used as an index of the number of migrating cells.
At this time, the test compound was added to the upper chamber at various concentrations together with THP-1 cells to inhibit cell migration (inhibition degree: IC
₅₀ (μM) was determined. The degree of inhibition is {(the number of migrated cells by MCP-1 in the case without addition of the test compound in the upper chamber)-(the number of migrated cells in the case without MCP-1 in the lower chamber) = 100%} and the inhibition of 50% The results are shown in Table 1, where the concentration of the compound showing the above was taken as IC ₅₀ .

[0040]

[Table 1]

[0041]

Example 2 Inhibition of MCP-1 binding to THP-1 cells
Measurement The ability of a test compound to inhibit the binding of MCP-1 to human premonocyte-derived leukemia cells THP-1 was measured by Zachariae.
Was performed according to the method of J. Exp. Med. (1990) 1
71 , 2177-82).

THP-1 cells were added to 5 × 10 ⁷ cells /
Assay buffer (RPMI 16
40% (Flow Laboratories) with 1% BSA, 20 m
MHEPES was added thereto), and 200 μl of the mixture was dispensed into each RIA tube (manufactured by Eiken Kagaku). [ ¹²⁵
I] MCP-1 (manufactured by NEN) in the above buffer 1
Dissolve to 10 μl (0.04n)
g of MCP-1) was added to each tube, and at the same time, the test compounds shown in Table 2 were added at various concentrations and incubated at 37 ° C. for 15 minutes. After centrifuging at 2000 rpm for 3 minutes, the supernatant was removed by suction, and 500 μl of a solution containing 1% BSA in PBS was added.
The procedure of centrifuging at rpm for 3 minutes and sucking and removing the supernatant was repeated 3 times, and ¹²⁵ I amount of the cells remaining after precipitation was measured with a γ counter. MCP-1 1 instead of test compound
The count when ng was added was subtracted as non-specific adsorption, and the count when no test compound was added was 10
The inhibitory ability of the test compound on the binding of [ ¹²⁵ I] MCP-1 to THP-1 cells was calculated as 0%. The results are shown in Table 2.

[0043]

[Table 2]

[0044]

Example 3 Production of tablets Compound No. A tablet containing 30 mg of the hydrochloride of 1 was produced according to the following formulation. Compound No. 1 (hydrochloride) 30 mg lactose 87 mg starch 30 mg magnesium stearate 3 mg

[0045]

Example 4 Preparation of Injectable Compound No. An injectable solution containing 0.3 mg of the hydrochloride salt of 2 was prepared according to the following formulation. Compound No. 2 (hydrochloride) 30mg Salt 900mg Distilled water for injection 100ml

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/40 ABL 9454-4C C07C 217/64 7457-4H C07D 209/43 209/08 9284-4C 307/83 (72) Inventor Noriaki Endo 4-3-2 Asahigaoka, Hino City, Tokyo Teijin Limited Tokyo Research Center

Claims (2)

[Claims] 1. The following formula [I]:[In the formula, R₁Is C₃~ C_FourThe branched lower alkyl group of
Representation; R₂Is hydrogen atom, halogen atom, C₁~ C_FourLow grade
Alkyl group, C₁~ C_FourLower alkoxy group, C₃~ C_Five
Lower cycloalkyl group, C₂~ C_FourLower alkenyl group,
C₂~ C_FourLower alkenyloxy group, C₂~ C_FourLow rank
Lucinyloxy group, C₂~ C_FiveLower acyl group or
Represents an ano group; R₃Is a hydrogen atom or C₁~ C_FourLow grade
Represents an alkyl group; R_FourIs a hydrogen atom, unsubstituted or
Converted C₁~ C_FourLower alkyl group, unsubstituted or substituted
Converted C₁~ C_FourLower alkoxy group, halogen atom,
C₂~ C_FiveLower acylamino group, C₂~ C_FiveLower acyl
Oxy group, hydroxyl group, C_Four~ C ₇Lower cycloalkyl urea
Group or C₃~ C₇Represents a lower dialkylurea group; R
_FiveIs a hydrogen atom, a halogen atom, or C₁~ C_FourLow rank
Represents a rualkyl group; or R₂And R₃Are together
Unsubstituted or substituted C_Five~ C₆Saturation or failure
May form a saturated carbocycle, or R₂And R₃But
Together, they are unsubstituted or substituted oxygen atoms in the ring
Alternatively, a 5-membered aromatic ring containing a nitrogen atom may be formed.
Yes. ] An aryloxypropanolamine derivative represented by
Conductor and its pharmaceutically acceptable acid adduct are active ingredients
As a cell migration inhibitor. 2. In the formula [I], R₁Is isopropyl
Represents a group, R₂And R ₃Together with unsubstituted C₆Tiredness
Represents a Japanese carbocycle, R_FourAnd R_FiveRepresents a hydrogen atom.
Described aryloxypropanolamine derivatives and
Contains the pharmaceutically acceptable acid adduct as an active ingredient
Cell migration inhibitor.