JPS6299372A - Compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to thiophene acetic acid derivatives, processes for their preparation, pharmaceutical compositions containing them and their use as medicaments.

According to the present invention, the following formula I [wherein R8 and R2 may be the same or different,
each represents a hydrogen atom or a linear or branched alkyl group containing 1 to 4 carbon atoms; Polycyclic groups (e.g., chenyl, furyl,
and its salts are provided.

It is recognized that certain compounds of formula (II) may have one or more asymmetric carbon atoms. It is therefore to be understood that the present invention relates to all isomeric forms of the compounds of formula I, and thus in particular encompasses compounds of formula (I) in optically active or racemic form.

The term "straight-chain or branched alkyl group containing 1 to 4 carbon atoms" as used herein refers to a methyl or ethyl group, or a straight-chain or branched propyl or butyl group. means.

The term "halogen atom" as used herein includes, for example, fluorine, chlorine or bromine atoms.

The term "trihalogenomethyl group" as used herein includes, for example, trifluoromethyl groups.

The term "alkoxy group" as used herein includes, for example, methoxy or ethoxy groups, or linear or branched propoxy or butoxy groups.

For pharmaceutical use, the salts mentioned are physiologically acceptable salts, but other salts can also be used, for example, in the preparation of compounds of formula I and their physiologically acceptable salts. Suitable salts include, for example, alkali metal salts such as sodium or potassium salts.

Preferred compounds according to the present invention include R1 representing an alkyl group, R2 representing a hydrogen atom or an alkyl group,
Examples include compounds of formula (2) in which A represents a phenyl group.

Particularly preferred compounds according to the invention are as follows.

N-hydroxy-α-methyl-5-benzoyl-2-thiopheneacetamide, N-hydroxy-α-methyl-5-benzoyl-2-thiophene-N-methylacetamide, N-hydroxy-
α-Methyl-5-benzoyl-2-thiophene-N-isopropylacetamide.

The compounds of the invention can be prepared, for example, by the following method, i.e., in the presence of a condensing agent such as N,N'-carbonyldiimidazole, where R1 and A are as defined above. The acid is expressed by the following formula ■ R, -NH-OH! (CI (Tll
) (wherein R1 is as defined above) and, if desired, converting the resulting compound into a salt. Such a method forms another feature of the invention.

This reaction is preferably carried out in the presence of an organic solvent such as dichloromethane.

The compound of formula (1) used as a starting material in the above method can be prepared, for example, according to the method described in British Patent No. 1,331,505.

The compounds of formula (1) obtained by the process of the invention can, if desired, then be converted into their salts, in particular physiologically acceptable salts, for example by conventional methods. Such salts can be prepared in situ in the reaction mixture without the need for intermediate isolation of the compound of formula I itself. Conversely, the salts of the compounds 2) obtained can then be converted into compounds of formula I or into other salts, if desired.

The compounds of the invention possess valuable pharmacological properties.

In particular, they were found to inhibit both the oxygenase arachidonic acid pathway and the boxygenase arachidonic acid pathway when tested. Furthermore, they were found to exhibit anti-inflammatory activity in vivo and in vitro, and also inhibited antibody-induced stenosis in guinea pig lungs in vitro. In view of these pharmacological effects,
The compounds of the invention are suitable for use as medicaments.

Therefore, the present invention provides a formula for use as a medicament.
and pharmaceutically acceptable salts thereof.

Among these compounds, particular mention may be made of compounds corresponding to formula I in which R1 represents an alkyl group, R1 represents a hydrogen atom or an alkyl group, and A represents a phenyl group, and pharmaceutically acceptable salts thereof.

Among the latter, compounds of the formula (3) whose compound names are as follows are mentioned.

N-hydroxy-α-methyl-5-benzoyl-2-thiopheneacetamide, N-hydroxy-α-methyl-5-benzoyl-2-thiophene-N-methylacetamide, N-hydroxy-
α-Methyl-5-benzoyl-2-thiophene-N-isopropylacetamide and salts of these compounds.

The medicament according to the invention can be used to treat patients suffering from or susceptible to inflammatory conditions, asthma or disorders of the immune system.

According to a further feature of the invention, at least one compound of formula I as defined above or a pharmaceutically acceptable salt thereof is used as active ingredient, together with one or more inert pharmaceutical carriers and/or auxiliaries. A pharmaceutical composition is provided containing the present invention.

For administration as a pharmaceutical, the compound of formula I, or its pharmaceutically acceptable salts, may be formulated with other active ingredients in a composition conventionally used in human medicine for oral, rectal or parenteral administration. I can do it. Pharmaceutical compositions may be in solid or liquid form using carriers and adjuvants conventionally used in the pharmaceutical industry. Preferred dosage forms include, for example, traditionally prepared tasteless tablets, sugar-coated tablets, capsules, granules, ampoules, herbal medicines and solutions for injection, for example.

The active ingredients may contain the auxiliaries customary in pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, fucoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glyfur, etc. It can be used in combination with various wetting, dispersing or emulsifying agents and/or preservatives.

More advantageously, the pharmaceutical composition may be formulated as dosage units, each dosage unit adapted to supply a given medicinal quantity of the active ingredient. The total daily dosage will vary depending on the compound used, but will generally range from 1 to 3 ootmp, preferably from 50 to 2001 R9, of active ingredient for administration to adults. However, such dosage varies depending on the underlying disease, route of administration, and patient.

The following examples are presented to illustrate the invention in more detail.

α-Methyl-5-benzoyl-2-thiophene acetic acid (5
A solution of g) in dry CH,Cl, (sod) was stirred vigorously and then treated with N,N'-carbonyldiimidazole (4,7,F). 10 at room temperature
After stirring for a minute, N-methylhydroxylamine hydrochloride (3.2 g') was added. Stirring was continued for 48 hours at room temperature, then the solvent was evaporated. The residue was dissolved in 40% ethyl acetate/petroleum ether and chromatographed (
sto, ) t, N-hydroxy-α-methyl-5
-Benzoyl-2-thiophene-N-methylacetamide (3,28p.

59%). mp-94-96°C.

IIIνoH-3200, c-o-1625Ql −
'NMR: (DMSO): 10.18 (11-i 1
H, OH), 7.81 (dd, 2H, aromatic), 7.5
0-7.75 (m, 4H.

aromatic), 713 (d, IH, aromatic), 4.75 (
q, IH.

CI ), 5.15 (s, 3H1M e N ), t4
4(d, 3H.

M e -C) Analysis C,,H,4No,8 Calculation:C62,4B,H4,89,N4.8/),51
t12% actual measurement: C62,29, I (5,23, N495
, S10. /'4% or carried out in a similar manner to 11, but
However, N-hydroxy-α-methyl-5-benzoyl-2-thiopheneacetamide was obtained using hydroxylamine Ifi acid salt as one of the reactants.

Amide Example 1 is carried out in a similar manner, but using N-isopropylhuman tetraxylamine hydrochloride as one of the reactants, N-hydroxy-α-methyl-5-benzoyl-2-
Thiophene-N-inpropylacetamide was obtained. m
p-114°C.

15 Niji oH-3100 Low 1, Shi c-o "" 16
50α-1NMR-: (DMSO): 961 (tr, I
H, OH), 7.8-7.85 (m, 2H1 aromatic),
7.75-77 <m14Hs aromatic), 71(d, I
H, aromatic →, 4.5-4.75 (m, 2H, CH),
t 4 (d, J-7Hz, 5 H, CH,), 1
．． 5-1.1 (2d.

J-7Hz, 6H1CH, isopropyl) Example 4 Tablets were prepared according to the following recipe.

N-Hydroxy-α-methyl-5-benzoyl-2-thiophene-N-methylacetamide --------
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−50 da (Excipient details: lactose, starch, talc, magnesium stearate) Example 5 Tablets were prepared according to the following formulation.

N-Hydroxy-α-methyl-5-benzoyl-2-thiophene-N-isobrobylacetamide ---------------------50 days test Excipients - Enough amount to make 300 tablets (excipient details: lactose, starch,
Talc, Magnesium Stearate) In the following examples, the "compound of Example 1" refers to N-hydroxy-α-methyl-5-benzoyl-2-thiophene-N-
Methylacetamide.

Example 6: Integration of Arachidonic Acid Metabolism The compound of Example 1 was evaluated for its ability to inhibit both the cyclooxygenase arachidonic acid pathway and the lipoxygenase arachidonic acid pathway using two different experimental procedures.

In the first experiment, rat peritoneal polymorphonuclear leukocytes were prelabeled with AH-arachidonic acid, incubated with the test compound, and then treated with calcium ionophore A23.
It was exposed to 187. The label released in 5-lipoxygenase or other substances was then measured by thin layer chromatography (TLC). IC, for the effect of the test compound on inhibiting total release of label into the supernatant and 5-lipoxygener. It is expressed as a value (in micromoles).

In the second method, guinea pig peritoneal polymorphonuclear leukocytes were preincubated with the test compound and then exposed to sH-arachidonic acid with calcium ionophores. This method does not rely on the binding of arachidonic acid to cellular phospholipids. The incubation products are separated into various arachidonic acid products by thin layer chromatography (TLC). The effect of the test compound was swamboxane B.
, (TxJ), 12-hydroxyhebutadecatriene 1 (HHT) and 5-hydroxyeicosatetraene d
The inhibition of the formation of (5-HETE) is expressed as IC, value (4 moles of mic).

Results Rat polymorphonuclear leukocytes Guinea pig polymorphonuclear leukocytes Methods reported by Messrs. J, Harvey-D, J. Osbaugh (J, Pharmaeol, M@thodB)
, 1983.9 [2], 147-55), the compound of formula (1) was added with '4C-arachidonic acid and calcium ionophore A23187 to inhibit the synthesis of eicosanoids in peritoneal worms of guinea pigs. It was tested as The results are listed in Table I.

Table 1 All compounds showed a strong inhibitory effect on the production of thromboxane B, but the latter two compounds also effectively inhibited the enzyme boxygenase.

The compound of Example 1 was tested in two in vivo tests, namely (1) carrageenan edema test and (ji) cell accumulation inhibition test in sponges, and in one in vitro test, namely PAF-induced polymorphonuclear leukocytes in rats. This was evaluated using a flocculation inhibition test.

In the carrageenan edema test, the test compound was orally administered 30 minutes before carrageenan administration, and edema was measured 3 hours after carrageenan administration.

In the sponge implantation model test, the test compound was orally administered 30 minutes and 6 hours after the sponge was implanted, and cells were collected 24 hours after the sponge was implanted. The results of these experiments are expressed as response inhibition rates (%).

Anti-inflammatory activity (inhibition rate %) Cell accumulation polymorphonuclear leukocyte aggregation 11* p<Q, O05 Example 9: Anti-asthma activity The compound of Example 1 inhibits antibody-induced contraction of guinea pig lungs in vitro Assessed ability.

Lungs were harvested from sensitized animals and irrigated via the bronchus. By orally administering the test compound 30 minutes prior to exposure to the antibody, the degree of inhibition of antibody-induced lung dysfunction in sensitized guinea pigs can be determined. The results obtained are shown below.

Anti-asthma activity (inhibition rate %) irrigated lungs lung dysfunction

Claims (9)

[Claims] (1) The following formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [Here, R_1 and R_2 may be the same or different, and each is a hydrogen atom or a straight line containing 1 to 4 carbon atoms. A represents a chain or branched alkyl group, and A represents a phenyl group (which has one or more halogen atoms or an alkyl, trihalogenomethyl, alkoxy, cyclohexyl, or heterocyclic group (e.g., thienyl, furyl,
and salts thereof. (2) The compound according to claim 1, wherein R_1 represents an alkyl group, R_2 represents a hydrogen atom or an alkyl group, and A represents a phenyl group. (3) Claim 1 in which the compound name is as follows:
or a compound of formula I according to paragraph 2. N-hydroxy-α-methyl-5-benzoyl-2-thiopheneacetamide, N-hydroxy-α-methyl-5-benzoyl-2-thiophene-N-methylacetamide, N-hydroxy-
α-Methyl-5-benzoyl-2-thiophene-N-isopropylacetamide and salts of these compounds. (4) A method for producing the compound and its salts according to claim 1, in which the following formula II▲ includes numerical formulas, chemical formulas, tables, etc.▼(II) (where R_1 and A is as described in claim 1) An acid of the following formula III R_2-NH-OH.HCl(III) (where R_2 is as described in claim 1) Process for the preparation of compounds of formula I and their salts, characterized in that the compounds obtained are reacted with the compound and, if desired, the obtained compounds are converted into salts. (5) The method according to claim 4, wherein the condensate is N,N'-carbonyldiimidazole and the reaction is carried out in the presence of dichloromethane as a solvent. (6) A drug comprising the compound of formula I according to claim 1 and its pharmaceutically acceptable salts. (7) Claim 6 consists of the compound of formula I as described in Claim 2 and its pharmaceutically acceptable salts.
Drugs listed in section. (8) N-hydroxy-α-methyl-5-benzoyl-
2-thiopheneacetamide, N-hydroxy-α-methyl-5-benzoyl-2-thiophene-N-methylacetamide, N-hydroxy-
The drug according to claim 6, comprising α-methyl-5-benzoyl-2-thiophene-N-isopropylacetamide and any of their pharmaceutically acceptable salts. (9) A pharmaceutical composition containing at least one drug according to any one of claims 6 to 8 as an active ingredient.