DK175445B1 - New 2-tetrazole-carboxamide benzothiophene(s) - for treating acute respiratory distress syndrome allergy, cardiovascular disorders, psoriasis, inflammation or migraine - Google Patents

Abstract

Benzothiophenes of formula (I) and their salts are new: X1, Y1 = O or S; R1, R2 = H or OR4; R4 = H, 1-6C alkyl or phenyl opt. mono- or disubstd. by halo, CF3, 1-6C alkyl, OH, 1-6C alkoxy, 1-6C alkylthio or COOR10; or R4 is opt. substd phenyl and is attached to the benzothiophene or benzofuran ring system through a 1-4C alkylene; R10 = H, 1-6C alkyl, NO2, NH2, mono-or di(1-6C alkyl)amino; R3 = R4 except H; (is when R11R2 = OH or alkoxy, then R3 cannot be alkyl or aralkyl, and both R1 and R2cannot be H. Also claimed is use of a pharmaceutical compsn. cont. (II), for treating acute respiratory distress, synchronie in humans. Y2, Y2 = O or S; R6, R7 = H, halo or OR8; R8 = R4 except 1-6C alkyl; if R1 and R2 cannot both be H; R5 = R8.

Description

DK 175445 B1

Use of benzothiophenes in the manufacture of drugs for the treatment of acute respiratory distress syndrome 5 Background of the Invention

Benzothiophene and benzof uranium compound Iser are e.g. disclosed in European Patent Application No. 0146243 and pending U.S. Patent Application Ser. No. 790,664, current U.S. Patent No. 4,703,053. Furthermore, European Patent Publication no.

10 69,521 and U.S. Patent No. 3,452,039 to various benzothiophene derivatives.

It has now been found that additional novel benzothiophene and benzofuran derivatives with selected substituents which are not present in view of the above references are capable of preventing the release of mediators including histamine and leukotrienes from basophils and mast cells, as well as prevent respiratory deficiency in neutrophils while providing activity useful for the treatment of cardiovascular disease, as well as anti-inflammatory, antipsoriatric, antiulcus, anti-migraine and especially as anti-allergic agents. That is, the novel agents of the present invention act as inhibitors of cell activation in the aforementioned diseases, and in the same manner as described in U.S. Patent Application Ser. No. 790,664, current U.S. Patent No. 4,703,053, the contents of which are considered part of the present disclosure.

Thus, the present invention relates to the use of novel compounds which are benzothiophene and benzofuran derivatives in the manufacture of pharmaceuticals.

Although U.S. Patent Application Ser. No. 790,664, current U.S. Patent No. 4,703,053, discloses compounds having activity for the prevention of respiratory deficiency in neutrophils, the present invention provides the use of selected benzothiophenes and benzofurans in the manufacture of drugs, in particular for the treatment of acute respiratory distress syndrome (ARDS) in mammals, especially humans, in need thereof, which treatment comprises administering an anti-ARDS effective amount of the selected benzothiophenes and benzofurans in unit dose form.

35

DK 175445 B1 I

2 I

Summary of the Invention

The present invention relates to a compound of formula (I) I

5 - © ΓΙΓλ-

Xl * 'CNH— ^ II

R: n ^ n I

Η I

and pharmaceutically acceptable salts thereof, wherein I

1) Xi and V, independently are oxygen or sulfur, I

2) R, and R2 are independent! is hydrogen or OR 4 wherein R 4 is hydrogen I

lower alkyl, aryl or aralkyl provided that both R 1 and R 2 are not simultaneously I

may be hydrogen and I

3) R 3 represents lower alkyl, aryl or aralkyl, provided that I

R 1 and R 2 cannot simultaneously be hydrogen; assuming that Rt and R2 I

independently represents hydroxy or alkoxy, then R 3 cannot be lower alkyl or I

aralkyl. IN

Thus, the present invention further relates to a pharmaceutical I

Composition for treating diseases or conditions such as acute respiratory I

distress syndrome, allergy, cardiovascular disease, ulcer, inflammation, psoriasis, I

ischemic diseases (stroke, TIA, hernia, embolism and thrombus) and I

migraine, which composition comprises an amount effective for treatment I

of each of these diseases or conditions of a compound of formula I, and an I

25 pharmaceutically acceptable carrier. IN

The invention further provides the use of the compounds of the invention I

in the manufacture of medicines for the treatment of allergies, cardiovascular diseases, I

inflammation, psoriasis or migraine in a mammal especially a human suffering from

30 which comprises administering a compound of formula I to I

unit dosage form. IN

Finally, the present invention provides the use of the compounds of I

the invention in the manufacture of drugs for the treatment of ARDS in a mammal;

35 in particular, a person suffering from it, by which treatment one is administered

compound of formula (II) I

DK 175445 B1 3 S ^^ Xl ^ CONH- {II _ Rt

5 H

and pharmaceutically acceptable salts thereof, wherein 1) X 2 and Y 2 independently represent oxygen or sulfur, 2) Re and R 7 independently represent hydrogen, halogen or OR 8, wherein Re represents hydrogen, lower alkyl, aryl or aralkyl, provided that both Re and R7 may not simultaneously be hydrogen, and 3) R5 represents hydrogen, lower alkyl, aryl or aralkyl, in unit dosage form.

15

Furthermore, the present invention provides a novel process for the preparation of the compounds of formula I, which comprises providing in step (1) a compound of formula (III),

R3Y1H III

wherein R 3 and Y are as defined above and NaH, in contact with a compound of formula (IV),

IV

R 1 is wherein X 1, R 1 and R 2 are as defined above and Hal is chlorine or bromine to give the compound of formula (IVa)

I DK 175445 B1 I

I 4 I

i ^ Y | R) lVa I

I ", _βλ jc?

yz> ^ Xl ^ cy, r, I

I 5 r2 I

step (2) treats a compound of formula IVa with aqueous base, I

Preferably in 1N NaOH, in methanol and tetrahydrofuran, to give the compound of I

In formula (V) I

i »'

I R2 R2

In which X1, Y1t Rt, R2 and R3 are as defined above and I

In step (3), the compound of formula V contacts a compound I

20 of formula (VI) in the presence of a condensing agent I

I / N I

HjN — & II I

I 25 I

I H I

I to give the compound of formula I.

In Step 1, a novel method and therefore itself is an aspect of the I

In the present invention. However, steps 1 and 2 can be performed by a reaction in a common container. IN

I 35 I

5 I

DK 175445 B1 I

Detailed Description of the Invention

Lower alkyl contains from 1 to 6 carbon atoms, including methyl, ethyl, propyl, butyl, I

pentyl, hexyl or isomers thereof. IN

Aryl is phenyl or substituted phenyl with one or two substituents, I

such as halogen, trifluoromethyl, lower alkyl, lower alkoxy, hydroxy, lower alkylthio, I

In COOR-io wherein R 10 is hydrogen or lower alkyl, nitro, arnino, substituted amino and I

In the like. IN

I 10 Lower alkoxy has from 1 to 6 carbon atoms including methoxy, ethoxy, propoxy, I

In butoxy, pentoxy, hexoxy or isomers thereof. IN

In Substituted amino, mono- or di-lower alkylamino. IN

In Halogen is chlorine, bromine, fluorine or iodine.

In Aralkyl, aryl is bonded to the benzothiophene or benzofuran ring system through a lower alkylenylcarbon chain that is straight-chain or branched with from 1 to 4L of carbon atoms.

I 20 I! In general, the novel process of the present invention for preparing the compounds of formula I is shown in Schemes A, B and I C.

In Scheme A (Step 1) I 25 I R, v, H "'" © riCL ^ I m x> CHd 30 I' - © τϊΓ-

Xl cy, Ry IV.

I DK 175445 B1 I Schedule B (Step 2) I ------- ^. YiRj OH- I, I "- ^ rn: I 10 I Schedule C (Step 3)

H

In HiN- ^ II

In 15 x · coH we

In each of compounds I, III, IV, IVa and V, the substituents X 1

I 25

The compounds of formula IV are prepared by analogy to the procedure described in Sudabeh Pakray and Raymond N. Castle in J. Heterocyclic Chem. 1986, I 23, p. 1571. The remaining starting materials, that is, the compounds of formula I III and of formula VI are commercially available or known, or may be prepared by known methods.

I A warm solution, of approx. 50 ° to 130 ° C, of the compound of formula IV, as defined above, in a solvent such as tetrahydrofuran (THF), ether, o-dichlorobenzene and mixtures thereof or the like, preferably THF, is rapidly added to a 0 ° -25 ° C solution 35 of RsY ^a in THF (formed by adding a solution of R3X, H in THF to a slurry of NaH, preferably 60% in oil dispersion in THF, at about 0 ° C to room temperature) or o-dichlorobenzene. The resulting mixture is stirred at ca. 0 ° C to room temperature for at least 15 min. and then reflux for from 0.5 to 100 hours, preferably for approx. 3 to 22 hours. Furthermore, the addition of tris [2- (2-methoxyethoxy) ethyl] amine described in US Patent No. 4,287,125 to the mixture 5 is refluxed for 0.5 to 3 hours, however optional. The resulting product of formula IVa may be isolated in conventional manner, such as by extraction, distillation, chromatography and the like, or may be used in further processing in crude form. .

The additional steps 2 and 3 above as shown in Schemes B and C are analogous to the saponification and conversion described for the compounds of the aforementioned US Patent Application Ser. No. 790,664, current U.S. Patent No. 4,703,053. whereby 5-aminotetrazole! react with the carboxylic acid portion of the present compound of Formula V.

Variations known to those skilled in the art are included in the descriptions either given above for steps 1 or 2 or described in U.S. Patent Application Ser. No. 790,664, current U.S. Patent No. 4,703,053.

The pharmaceutically acceptable salts of the compounds of formula I of the present invention are also as described for the compounds of U.S. Patent Application Ser. No. 790,664, current U.S. Patent No. 4,703,053, or as understood by one of ordinary skill in the art. See, e.g. "Pharmaceutical Salts" by S. M. Berge et al. in The Journal of Pharmaceutical Sciences. Vol. 66, No. 1, January 1977, pp. 1-19. 1 2 3 4 5 6 7 8 9 10 11

The anti-allergy activity of the compounds of formula I, according to the present invention, is determined by the well-known Schultz-Dale method 3 described in N. Chand et al. Aoents and Actions. 8, 171 (1978) or by 4

Herxheimer in vivo anti-allergy test, described in H. Herxheimer J. Phvsiol.

5 (London), Vol. 117, 251 (1952).

6 7

As a result of this anti-allergy activity, the compounds of formula I are useful for treating an allergic hypersensitivity reaction (AHR) with wide symptoms.

9 For example. These symptoms may include pruritis, erythema, edema, dermatitis, lacrimation, nasal discharge, cough, sneezing, nausea, vomiting, diarrhea, respiratory distress, pain, 11 inflammation and in severe cases anaphylactic shock, circulatory collapse and even death. AHR is found in humans as well as in other animals suffering from bronchial

I DK 175445 B1 I

I 8 I

In asthma, seasonal polyinosis (eg hay fever), allergic rhinitis, contact allergies (poison I

In sumac and ivy, etc.), urticaria, allergic conjunctivitis. food allergies and I

anaphylactoid reactions. IN

In the case of an AHR, an antigen or a cytokine affects the cell membrane of a mast cell I

You react with an antibody or receptor to initiate reactions in the mast cell I

which ultimately causes the formation and release of mediators (bioactive I

In compounds) such as bradykinin, slow-reacting anaphylaxis (SRS-A), I

In histamine, serotonin (5HT), thromboxanes, prostaglandins or others not on I

In the 10 present known connections. The mediator or mediators are released from I

In the mast cell, where it is attached to suitable receptor sites (eg, smooth muscle),

resulting in AHR attack symptoms. Various methods are used for relief I

I of the symptoms of AHR. However, it is not known which mechanism is activated in I

In connection with the anti-allergic use of the compounds of formula I according to I

In the present invention. IN

Pharmaceutical compositions are prepared from compounds of formula I and salts I

Hence, with inert pharmaceutical carriers. The compositions may be either solid I

In or liquid. IN

I 20 I

I An ordinary doctor or veterinarian can easily determine an individual who exhibits AHR I

In symptoms. Regardless of the route of administration chosen, the compounds of I are formulated

In the present invention on pharmaceutically acceptable dosage forms by means of I

conventional pharmaceutical methods known in the art. IN

I 25 I

The compounds may be administered in oral unit dosage forms such as tablets, capsules, I

In pills, liquids, syrups, powders or granules. They can also be administered rectally

In or vaginally in forms such as suppositories or bougies, they may also be introduced

Parenterally (eg, subcutaneously, intravenously or intramuscularly) using I

In 30 forms known in the pharmaceutical art. They are also introduced directly into an I

In the affected area (eg in the form of eye drops or by inhalation). For the treatment of I

In AHR-induced conditions, such as erythema, the compounds of the I

The present invention is also administered topically in the form of ointments, creams, gels or I

In the like. In general, the preferred route of administration is oral except for acute I

In treatment where the parenteral route is preferred. IN

DK 175445 B1 9

An effective but nontoxic amount of the compound is used for treatment. A conventional physician or veterinarian can readily determine and prescribe the effective amount of the anti-AHR agent to prevent or halt the development of the condition. For this, the doctor or veterinarian could use relatively small doses initially and then increase the dose 5 until a maximum response is achieved.

Initial doses of the compounds of the invention having formula I or II are usually in the range of 10 mg to 2 g per day. daily orally, preferably 10 mg to 500 mg per day. dose orally administered from 1 to 4 times daily, or as needed. When other forms of administration are used, equivalent doses are administered.

Preferably, the pharmaceutical composition of compounds of formula I or II is in unit dosage form. The amount of active compound in a unit dose composition may be varied or adjusted from 1 mg to 500 mg, preferably from 1 to 200 mg according to the particular application and potency of the active ingredient. The compositions may also contain other compatible therapeutic agents if desired.

The compounds of formula II have been found to be particularly useful in the treatment of ARDS, as demonstrated by an assay demonstrating the inhibition of oxygen radical formation of human neutrophils for representative compounds of formula II by two assays. One assay provides IC 50 values for the inhibition of superoxide formation. DeChatelet, L R., Shirley, P. S. and Johnson, R. B. 1976. Effect of phorbol myristate acetate on the oxidative metabolism of human polymorphonuclear leukocytes. Blood 47: 545-554. The second assay is a widely recognized in vivo assay for the detection of activity useful in the treatment of ARDS. The in vivo assay is described in J. Clin. Invest., Vol. 69, May 1982, pp. 1126-1135.

The representative compounds tested in the in vitro assay for the inhibition of superoxide formation are: 30 1. 5-Methoxy-3- (1-methylethoxy) -N-1H-tetrazol-5-yl-benzo [b] thiophene-2 carboxamide.

2. 6-Methoxy-3- (1-methylethoxy) -N-1H-tetrazol-5-yl-benzo [b] thiophene-2-carboxamide.

3. 5-Methoxy-3 - [(1-methylethyl) thio-N-1H-tetrazol-5-yl] -benzo [b] thiophene-2-carboxamide.

4. 6-Methoxy-3- (1-methylethoxy) -N-1H-tetrazol-5-yl-2-benzofurancarboxamide.

5. 3-Benzyloxy-5-methoxy-N-1H-tetrazol-5-yl-benzo [b] thiophene-2-carboxamide.

6. 5-Methoxy-3-phenoxy-N-1H-tetrazol-5-yl-benzo [b] thiophene-2-carboxamide.

I DK 175445 B1 I

I 10 i

The activity for each of these compounds, as numbered above, is expressed as I

In IC 50 values for the inhibition of superoxide formation and are shown in subsequent Table A: I

I 5 I

I TABLE A I

I 10 The above IC50 (μΜ) I

In connection R6 R5 X Y inhibition of 02-1

I No. formation from neutrophils I

I 15 1 5-methoxy 1-methylethyl SO 19 I

I 2 6-methoxy 1-methylethyl SO 37 I

I 3 5-Methoxy 1-methylethyl SS 23 I

I 4 6-methoxy 1-methylethyl O 75 I

5-methoxy benzyl SO 23 I

I 20 6 5-methoxy phenyl SO 10 I

In addition, the examples of compounds listed in the following Table A1 also show I

activity with IC 50 values for inhibition of superoxide formation. IN

I 25 I

I TABLE A1 I

In IC »(µΜ) I

In Example R5 Re inhibition of 02-1

I No. formation from neutrophils I

In C21C Ph 5,6-diOMe 6 I

I 35 C21D Ph 6-OMe> 100 I

In C21A CH2Ph 5,6-diOMe 40 I

I C20A CHMe2 5-OH 48 I

Therefore, the compounds of formula II have now been found to be particularly useful for I

In the treatment of ARDS. as shown by inhibition of cobra venom factor (CVF) induced I

DK 175445 B1 11 lung lesion in rats using compound # 1 above in the in vivo assay shown as follows in Table B:

TABLE B

5 Inhibition of CVF-induced lung injury in rats of compound # 1 above

Treatment Number of animals Lung lesion Protection (x ± SEM)% Lesion inhibition 10 ____; _

Exp. A.

Saline (control) 5 0.20 ± 0.01 CVF treatment 7 1.45 ± 0.19 CVF + Compound No. 1. 5 0.48 ± 0.08 76 iv * CVF + Compound No. 1, 4 0 , 73 ± 0.06 58 iP · ** 20 * Compound # 1 above was administered intravenously (20 mg / kg) 10 minutes before intravenous injection of CVF (20 mg / kg) "• Compound # 1 above was injected intraperitoneally (20 mg / kg) 20 minutes before CVF.

25

EXAMPLES EXAMPLE 1 3-Benzyloxy-5-methoxy-N-1H-tetrazol-5-yl-benzofb1-thiophene-2-carboxamide Step 1. A solution of 13.1 g (120.8 mmol, 2.8 equivalents) benzyl alcohol in 35 ml dry tetrahydrofuran is added dropwise over 10 minutes to a slurry at room temperature of 4.3 g (107.5 mmol, 2.5 equivalents) 60% NaH oil dispersion in 65 ml of tetrahydrofuran under nitrogen atmosphere. The reaction mixture is stirred for 15 minutes and then cooled on an ice-water bath. A warm solution of 11.4 g (43.7 mmol) of 3-chloro-5-methoxy-benzo [b] thiophene-2-carbonyl chloride (prepared by the procedure described by Sudabeh Pakray and Raymond N. Castle (Heterocyclic Chem. 1986, 23, 1571) in 95 ml of tetrahydrofuran is rapidly added to the 0 ° C 40 cold reaction mixture. The reaction mixture is stirred at 0 ° C for 15 minutes, heated at reflux for three hours and allowed to cool to room temperature before

I DK 175445 B1 I

I 12 I

It is poured into 700 g of ice water. The resulting mixture is extracted with diethyl ether I

I (4 x 200 ml). The combined extracts are washed with saturated aqueous NaHCC> 3 (100 mL), I

In water (100 ml) and saturated aqueous NaCl, dried over Na 2 SO 4 and concentrated in vacuo

I to give a brownish yellow solid. The material was used, as it were, for it

In 5 subsequent reaction. A sample of the residue is recrystallized from ethanol-water to · I

In obtaining analytically pure benzyl-3-benzyloxy-5-methoxybenzo [b] -thiophene-2- I

In carboxylate as a white crystalline solid: m.p. 66-67 ° C. IN

In Step 2. A solution of the above crude solid in aqueous 1N NaOH (80 mL), methanol I

I 10 (80 ml) and tetrahydrofuran (80 ml) are heated at reflux for 1.5 hours and allowed to stand.

I for cooling to room temperature. The mixture is concentrated in vacuo and collected in 700 ml of I

In hot aqueous 1N NaOH and 300 ml hot methanol, filter and extract with hexane I

I (3x). The aqueous solution is treated with 500 g of ice, followed by the addition of I

In concentrated HCl until acidity. The resulting precipitate is collected at 1

In vacuo filtration and recrystallized from toluene to give 6.5 g (13.7 g theoretically, I

In 47%) analytically pure 3-benzyloxy-5-methoxy-benzo [b] thiophene-2-carboxylic acid, as an I

In white crystalline solid: m.p. 150 ° C. IN

In Step 3. A solution of 5.6 g (17.2 mmol) of the above carboxylic acid and 3.5 g of I

In 20 (21.4 mmol, 1.2 equivalents) 1, T-carbonyl-dimidazole in 110 ml of acetonitrile is heated

Reflux for one hour under nitrogen. The reaction mixture is allowed to cool to 1

room temperature and treated with 1.8 g (21.4 mmol, 1.2 equivalents) anhydrous 5- I

In aminotetrazole and 4.4 g (43.1 mmol, 2.4 'equivalents) of triethylamine. IN

In the reaction mixture is refluxed for 3.75 hours and then poured onto 1

In 1000 g of ice water. The aqueous solution is acidified with aqueous 10% HCl and filtered. The ten

Solid is recrystallized from dimethylformamide water and from 2-methoxyethanol to 1

To obtain 2.7 g (6.8 g theoretically, 40%) of analytically pure carbamoyl tetrazole as an I

In pale yellow solid: m.p. 206E-207 ° C. IN

In 5,6-dimethoxy-3- (phenylmethoxy) benzolbiolthiodenh-2-carboxylic acid I

I Of the corresponding 2-carbonyl chloride using those of Example I

In step 1 and step 2 above, I recrystallization methods described above

In isopropanol, 5,6-dimethoxy-3- (phenylmethoxy) benzo [b] thiophene-I

In 2-carboxylic acid: m.p. 188 ° C, (dec.). IN

I 35 I

EXAMPLE 2 5-Methoxy-3-phenoxy-N-1H-tetrazol-5-yl-benzophyllthiophene-2-carboxamide Step 1. A solution of 12.2 g (130.1 mmol, 3.0 equivalents) ) Phenol in 40 ml o-5 dichlorobenzene is carefully added to a mechanically stirred slurry of 5.2 g (129.5 mmol, 3.0 equivalents) 60% NaH oil dispersion in 70 ml o-dichlorobenzene under nitrogen atmosphere. The reaction mixture is stirred for 30 minutes and treated with a warm solution of 11.4 g (43.7 mmol) of 3-chloro-5-methoxy-benzo [b] thiophene-2-carboxyl chloride (prepared by the procedure described of 10 Sudabeh Pakrav and Raymond N. Castle in J. Heterocyclic Chem .. 1986. 23.1571) in 50 ml of o-dichlorobenzene and 50 ml of tetrahydrofuran. The resulting mixture is heated at 130 ° -155 ° C for one hour and then treated with 1.4 g (4.4 mmol, 0.1 equivalents) of tris [2- (2-methoxyethoxy) ethyl] amine and heated at 130 ° -135 ° C for a further 22 hours. The reaction mixture is allowed to cool to room temperature and poured onto 600 ml of chloroform and 500 ml of cold aqueous 0.5N NaOH and the layers are separated.

The aqueous layer is extracted with chloroform (three times). The combined organic layers are washed out with cold aqueous 1N NaOH, aqueous 3N HCl and saturated aqueous NaCl, dried over Na 2 SO 4, filtered and concentrated in vacuo to ca. 200 ml. The solid is isolated by vacuum filtration and washed with aqueous 1N NaOH (twice), water (twice) and 20 diethyl ether (twice) and dried to give 8.0 g (16.5 g of theory, 48%) of phenyl 5 -methoxy-3-phenoxy-benzo [b] thiophene-2-carboxylate as a pale yellow solid. The material is sufficiently pure for use in the subsequent reaction. A toluene recrystallized sample gives analytically pure product as a white crystalline solid: m.p. 198eC.

25

Step 2. Using the procedure described in Step 2 of Example 1, 7.9 g (21.0 mmol) of the above product gives 5.1 g (6.3 g of theory, 81%) of analytically pure 5-methoxy-3 -phenoxy-benzo [b] thiophene-2-carboxylic acid as a pale yellow crystalline solid: m.p. 197 ° C (ethyl acetate-hexane).

30

Step 3. Using the procedure described in Step 3 of Example 1, 4.0 g (13.3 mmol) of the above product gives 3.8 g (4.9 g of theoretical, 78%) of analytically pure carbamoyltetrazole as a white solid : m.p. 251 ° -252 ° C (2-methoxyethanol).

35

DK 175445 B1 I

14 I

5,6-Dimethoxy-3-phenoxy-benzofibthiophene-2-carboxylic acid and 6'-methoxy-3-phenoxy-I

benzofibthiophene-2-carboxylic acid I

Further, it is prepared from the corresponding 2-carbonyl chloride using the I

5 of Example 2, steps 1 and 2 described by recrystallization from ethanol · I

5.6-Dimethoxy-3-phenoxy-benzo [b] -thiophene-2-carboxylic acid: m.p. 208 ° C, (dec.), Which I

is sufficiently pure for the subsequent step, as well as 6-methoxy-3-phenoxy-I

benzo [b] thiophene-2-carboxylic acid: m.p. 219 ° -220 ° C, (dec.). that is sufficiently clean for you

the subsequent step. IN

10 I

EXAMPLE A1 I

3-Chloro-6-methoxy-benzophyllothiophene-2-carbonyl chloride I

Thionyl chloride (73 ml, 1.0 mol) is added dropwise to a stirred suspension of 4- I

methoxycinnamic acid (36.8 g, 0.20 mol) in pyridine (1.6 ml, 0.02 mol) and chlorobenzene (200 L

ml) under argon. The mixture is heated to reflux. After 72 hours, I filter

the mixture and "stripped" for volatiles under reduced pressure. The residue is dissolved

in boiling methyl t-butyl ether (650 ml), filtered, concentrated to 500 ml and cooled to 1

To give the pure product (22 g): m.p. 120 ° -121eC. (see Ried et al., Ann, Chem. I

(1980) 1424-7.) I

EXAMPLE A2 I

25 I

3.7-dichloro-6-methoxy-benzo [b] thiophene-2-carbonyl chloride I

Chlorine (24 g) is bubbled in a stirred suspension of 3-chloro-6-methoxy-benzo [b] thiophene-2-

carbonyl chloride (9.2 g, 35 mmol) in chloroform (200 ml) over a period of 30 l

minutes. After a further 45 minutes of stirring at room temperature, I "stripped"

The mixture for volatiles under reduced pressure. The residue is recrystallized from I.

tetrahydrofuran (100 ml) to give the pure product (6.6 g): m.p. 174 ° -175 ° C. IN

EXAMPLE A3 I

3-Chloro-5,6-dimethoxy-benzoribthiophene-2-carbonyl chloride I

DK 175445 B1 15

Thionyl chloride (18.3 ml, 0.25 mol) is added dropwise to a stirred suspension of 3,4-dimethoxy cinnamic acid (10.4 g, 0.05 mol) in pyridine (0.4 ml, 0.005 mol) and chlorobenzene (50 ml) under argon. The mixture is heated under vigorous reflux for 72 hours and then allowed to cool. The suspended solid is filtered off, rinsed with 5-methyl-t-butyl ether and dried. Recrystallization from tetrahydrofuran (135 ml) gives the product (5.7 g): m.p. 191e ~ 199 ° C. A small sample was recrystallized from the same solvent for analytical purity: m.p. 204 ° -205 ° C. (See Wright and Brabander, J.

Hel Chem. (1971) 711-4.) EXAMPLE A4 3-Chloro-6- (Dhenylmethoxy) -benzophenothiophene-2-carbonyl chloride Thionyl chloride (10.6 ml, 0.15 mol) is added dropwise to a stirred suspension of 4-15 benzyloxycinnamic acid ( see Doherty, J. Am. Chem. Soc. 77 (1955) 4887-4892) (7.3 g, 0.03 mol) in a mixture of NN-dimethylformamide (2.2 ml, 0.03 mol), pyridine (0.24 ml, 0.003 mol) and chlorobenzene (40 ml) under argon. The mixture is heated to reflux for 24 hours, then cooled and filtered. The filtrate is "stripped" for volatiles under reduced pressure and the residue is suspended in ether and filtered to give the product (3.7 g): m.p. 132e-134 ° C.

3-Chloro-5-methoxy-6- (phenylmethoxy) benzophenothiophene-2-carbonyl chloride Prepared by the procedure of Example A4 using 3-methoxy-4-benzyloxy-cinnamic acid (Pearl and Beyer, J, Orq, Chem. 16 (1951 216) (25.0 g, 25 88 mmol) with recrystallization of the residue from toluene gave 3-chloro-5-methoxy-6- (phenylmethoxy) benzo [b] thiophene-2-carbonyl chloride (13.7 g): m.p. . 144 ° -152eC.

EXAMPLE A5 3-Chloro-6-phenoxy-benzophylthiophene-2-carbonyl chloride

Prepared by the procedure described in Example A4 using 4-phenoxycinnamic acid (Watanabe et al., J. Med. Chem. (1980) 50-59) (3.1 g, 0.013 mol). Recrystallization of the residue from methyl t-butyl ether (50 ml) gives the product (2.4 g): m.p. 121 * -123 ° C.

I DK 175445 B1 I

I 16 I

In Example A6 I

I 3-Chloro-5- (phenylmethoxy) -benzoylthiophene-2-carbonyl chloride I

I Prepared by the method described in Example A4 under I

In the use of 3-benzyloxycinnamic acid (see Example A4 above) (4.0 g, 0.016 mol). IN

In recrystallization of the residue from toluene (18 ml), the product (1.5 g) gives: m.p. 139 ° · I

I 142X. IN

EXAMPLE A7 I

I 3-Chloro-5-phenoxy-benzophenothiophene-2-carbonyl chloride I

I Prepared by the method described in Example A4 under I

Using 3-phenoxycinnamic acid (see Brittelli, J. Org. Chem. 46 (1981) 2514-2520) I

(4.4 g, 0.018 mol). Recrystallization of the residue from methyl t-butyl ether (50 ml) I

You give the pure product (2.3 g): m.p. 117 ° -119 ° C. IN

In Example B8 I

I 20 I

In 6-methoxy-3- (1-methylethoxy) benzofibthiophene-2-carboxylic acid I

In Isopropanol (16.8 g, 280 mmol) is added dropwise to a stirred suspension of I

In sodium hydride (11.2 g of a 60% dispersion in mineral oil, 280 mmol) in tetrahydrofuran I

I (50 ml) under argon. After 20 minutes, an I is gradually added over 5 minutes

In solution of 3-chloro-6-methoxy-benzo [b] -thiophene-2 * carbonyl chloride (24.2 g, 93 mmol) I

Into hot tetrahydrofuran (180 ml) and the mixture is heated to reflux. After I

For 16 hours, the mixture is cooled and Mstrippesn for solvent under reduced pressure. IN

The residue is layered between water (600 ml) and ether (300 ml). The teams are separated and the I

aqueous phase is extracted twice with ether (200 ml). The combined ether extracts I

30 is washed with saturated brine, dried over MgSO 4 and "stripped" for solvent I

under reduced pressure, leaving the crude ester as a syrup that also

contains mineral oil. The syrup is stirred in a mixture of methanol (20 ml) and 1N I

sodium hydroxide (100 ml) and heated at reflux. After 12 hours, stir

the mixture in water (600 ml) and extracted twice with ether (150 ml). The watery I

The solution is stirred and acidified with concentrated HCl and the resulting precipitate I

Is filtered off, rinsed thoroughly with water and dried to give the product (11.7 g): m.p. 155 DEG-156 DEG C. (dec.).

The following compounds were prepared from the corresponding 2-carbonyl chlorides using the procedure described in Example B8.

10 R-f ^ X ^ -COOH

Example R (R 1 and / or R 2) m.p. ° C

15 __ B9 5.6-DiOMe 169-170 (dec.) BIO 6-OMe, 7-CI 191-192 (dec.) B11 6-OBn 163-164 20 B12 * 6-0 Ph 161-162 (dec.) B13 5-OBn 160-161 B14 5-OPh 191-192 (dec.) Me is methyl, Bn is benzyl, Ph is phenyl.

* See the following description for procedure.

EXAMPLE B14A 3- (1-Methylethoxy) -5-methoxy-6- (phenylmethoxy) -benzophenothiothene-2-carboxylic acid Further, using the procedure of Example B8, is prepared from the corresponding 2-carbonyl chloride with recrystallization from ethanol pure 3- ( 1-methylethoxy) -5-melhoxy-6- (phenylmethoxy) -benzo [b] -thiophene-2-carboxylic acid: m.p. 183 ° C, (dec.).

35 40 I DK 175445 B1

I 18 I

In Example B12 I

6-Dhenoxy-3- (1-methylethoxybenzorbylthiothene-2-carboxylic acid I

In Isopropanol (1.6 ml, 21 mmol) is added dropwise to a stirred suspension of I

In sodium hydride (0.85 g of a 60% dispersion in mineral oil, 21 mmol) in tetrahydrofuran I

I (25 ml) under argon. After 30 minutes, 3-chloro-6-phenoxy-benzo [b] thiophene-2-I is added

In carbonyl chloride (2.3 g, 7 mmol) and the mixture is heated at reflux. After I

For 18 hours, the mixture is cooled and "stripped" of solvent under reduced pressure. IN

In the residue, layer between water (100 ml) and ether (60 ml). The teams are separated and the I

In 10 aqueous phase, extract twice with ether (50 ml). The combined extracts are washed

With saturated saline, dried over MgSO 4 and "stripped" for solvent under I

reduced pressure, leaving the crude ester as a syrup that also contains I

In mineral oil. The syrup is stirred in a mixture of methanol (5 ml) and 1N sodium hydroxide I

I (10 ml) and heated at reflux. After 24 hours, the mixture is poured into water I

In 15 (300 ml) and the precipitate is filtered off, rinse three times with water, then three times I

In ether, resuspend in water and make acidic with concentrated HCl. The precipitate I

Filter off, rinse thoroughly with water and dry: m.p. 16Γ-162 * Ό, (dec.). IN

EXAMPLE C15 I

In 6-methoxy-3-n-methylethoxy-1-N-1H-tetrazol-5-yl-benzophyllthiophene-2-carboxamide I

Carbonyl diimidazole (3.8 g, 23 mmol) is added to a stirred solution of 6-methoxy-3- (1-

In methylethoxy) benzo [b) thiophene-2-carboxylic acid (5.4 g, 20 mmol) in tetrahydrofuran (75 L

(25 ml) under nitrogen and the mixture is heated at reflux. After 75 minutes I

To it is added 5-aminotetrazole (1.66 g, 20 mmol). After another three hours under I

At reflux, the mixture is stirred in water (350 ml) and acidified with concentrated HCl. IN

The resulting precipitate is filtered off, rinsed with water and dried. Recrystallization from I

In DMF / methanol gave the pure product (4.0 g): m.p. 233-234 ° C, (dec.). IN

I 30 I

The following compounds were prepared from the corresponding 2-carboxylic acids under I

Using the procedure described in Example C15. IN

I 35 I

DK 175445 B1 19 - © £ ^ * - 0 5

H

Example R (R 1 and / or R 2) m.p. "C

10 C16 5,6-DiOMe 247-248 (dec) C17 6-OMe, 7-CI 251 (dec) C18 6-OBn 245 (dec) 15 C19 6-OPh 210 (dec) C20 5- OBn 225-226

Me, Bn and Ph are as defined above.

20

EXAMPLE C20A

3- (1-Methylethoxy) -5-hydroxy-N-1H-tetrazol-5-yl-benzofibthiophene-2-carboxamide A hot slurry of 3- (1-methylethoxy) -5- (phenylmethoxy) -N-1H- tetrazol-5-yl-benzo [b] thiophene-2-carboxamide (1.9 g, 5 mmol) and 20% palladium-on-carbon (0.5 g) in acetic acid (250 ml) are shaken under hydrogen (50 psig) a Parr apparatus. After three hours, additional catalyst (0.5 g) is added and the mixture is shaken at ambient temperature for 15 hours. The catalyst is removed by filtration and rinsed with hot acetic acid (200 ml). The filtrate is "stripped" of solvent under reduced pressure, and two portions (50 ml) of toluene are added, then "stripped" from the residue to leave the crystalline product. Recrystallization from methanol gave the pure 3- (1-methylethoxy) -5-hydroxy-N-1H-tetrazol-5-yl-benzo [b] thiophene-2-carboxamide (0.7 g): m.p. 258 ° C, (dec.).

By analogy to the procedure of Example C20A, the following compound of the above formula, Example C16-C20, was prepared.

35

I DK 175445 B1 I

I 20 I

In Example R m.p. ° C

I 5 C21 5-OPh 219 (dec.) I

In Ph is as defined above. IN

In addition, it was prepared from the corresponding 2-carboxylic acid using the I

In the procedure described in Example 15, compounds C21A, C21C and C21D. IN

In Example C21A I

I 15 I

In 5,6-Dimethoxy-3- (Dhenylmethoxy) -N-1H-tetrazole-5-yl-benzophthiothioene-2-carboxamide I

In m.p. 232 ° C (dec.). IN

I 20 I

In Example C21B I

In 3- (1-Methylethoxy) -5-methoxy-6-hydroxy-N-1H-tetrazol-5-yl-benzoflb-thiophene-2-

In carboxamide I

I 25 I

A slurry of 3- (1-methylethoxy) -5-methoxy-6- (phenylmethoxy) -N-1H-tetrazole-5-

In yl-benzo [b] thiophene-2-carboxamide imidazole salt (1.55 g, 3 mmol) and 20% palladium-on-I

In carbon (0.5 g) in acetic acid (250 ml), shake under hydrogen (50 psig) in a Parr apparatus I

I at 40 ° C. After 19 hours, an additional 0.5 g of catalyst and acetic acid (250 ml) are added

For 30 hours, shaking is continued at 50 ° C for 33 hours. The catalyst is filtered from the cooled I

In mixture and rinse with acetic acid. The solvent "stripped" filtrate under · I

At reduced pressure, leaving the crystalline product. Recrystallization from I

In methanol, the pure 3- (1-methylethoxy) -5-methoxy-6-hydroxy-N-1H-tetrazol-5-yl-1

In benzo [b] thiophene-2-carboxamide (0.3 g): m.p. 245 ° C, (dec.). IN

I 35 I

DK 175445 B1 21

EXAMPLE C21C

5,6-Dimethoxy-3-phenoxy-N-1H-tetrazol-5-yl-benzo [bthiophene-2-carboxamide is prepared analogously to the procedure in C15 above.

5 m.p. 272 ° C (dec.).

EXAMPLE C21D

6-Methoxy-3-phenoxy-N-1H-tetrazol-5-yl-benzophylthiophene-2-carboxamide is prepared analogously to the procedure in C15 above.

mp. 271®-2 ° C, (dec.).

EXAMPLE B22 6-Methoxy-3- (phenylmethoxy) -benzophyllthiophene-2-carboxylic acid 20 Benzyl alcohol (6.0 ml. 58 mmol) is added dropwise to a stirred suspension of sodium hydride (2.3 g of a 60% dispersion in mineral oil, 58 mmol). tetrahydrofuran (15 ml) under argon. After 20 minutes, a solution of 6-methoxy-3-chlorobenzo [b] thiophene-2-carbonyl chloride (5.0 g, 19 mmol) in hot tetrahydrofuran (60 ml) is added over 5 minutes and the mixture is heated under reflux. After 16 hours 25 the mixture is cooled and "stripped" of solvent under reduced pressure.

The residue is layered between water (300 ml) and ether (150 ml). The layers are separated and the aqueous phase is extracted twice with ether (100 ml). The combined ether extracts are washed with saturated brine and dried over Mg $ 04, then stripped of solvent under reduced pressure, leaving the crude ester as a syrup containing mineral oil as well. The syrup is stirred in a mixture of methanol (10 ml) and 1N sodium hydroxide (38 ml) and heated under reflux. After four hours, the heating is switched off and the methanol is removed under reduced pressure.

The residue is diluted with water (300 ml) and extracted twice with ether (100 ml). The aqueous solution is stirred and acidified with concentrated HCl and the precipitate is filtered off, rinsed with water and dried. Recrystallization from ethanol gave the pure product (2.1 g): m.p. 194 ° C, (dec.).

. - · - - '

22 I

DK 175445 B1 I

EXAMPLE C23 I

6-Methoxy-3- (Dhenylmethoxy) N-1H-tetrazol-5-yl-benzo [b] thiophene-2-carboxamide I

Prepared analogously to the procedure described for Example C15 under I

Using 6-methoxy-3- (phenylmethoxy) benzo [b] thiophene-2-carboxylic acid (1.5 g,

5 mmol). Recrystallization from DMF / MeOH gave the pure product (1.2 g): m.p. 222C, I

(Dec.). IN

EXAMPLE C24 I

3- (1-Methylethoxy) -5-methoxy-6- (phenylmethoxy) -N-1H-tetrazol-5-yl-benzoyl-1

thiophene-2-carboxamide, imidazole salt I

Carbonyl diimidazole (0.7 g, 4 mmol) is added to a stirred solution of 3- (1- I

Methyl methoxy) -5-methoxy-6- (phenylmethoxy) benzo [b] thiophene-2-carboxylic acid (1.6 g, I

4 mmol) in tetrahydro-uranium (50 ml) under nitrogen and the mixture is heated under 1

reflux. After 75 minutes, 5-aminotetrazole (0.36 g, 4 mmol) is added. After I

for another three hours at reflux, the mixture is stirred in water (500 ml) and the mixture is stirred

the suspended solid is filtered off, rinsed twice with ethanol, twice with ether I

20 and dried to give 3- (1-methylethoxy) -5-methoxy-6- (phenylmethoxy) -N-1H-1

tetrazol-5-yl-benzo [b] thiophene-2-carboxamide, imidazole salt (1.6 g): m.p. 270 ° C, (dec.). I 1

Claims (15)

Use in the manufacture of a medicament for the treatment of acute respiratory distress syndrome in humans of a compound of formula II: wherein R 1) X 2 and Y 2 are independently oxygen or sulfur; Use according to claim 1, characterized in that X2 is sulfur. 2. R6 and R7 are independently halogen, hydrogen or ORa, wherein Re is hydrogen, lower alkyl, aryl or aralkyl, provided that both R6 and R7 cannot simultaneously be hydrogen, and Use according to claim 1, characterized in that Y 2 is oxygen. 3. R 5 is hydrogen, lower alkyl, aryl or aralkyl in unit dosage form. 20 Use according to claim 3, wherein the compound II is 5,6-dimethoxy-3- (phenylmethoxy) -N-1H-tetrazol-5-yl-benzo [b] thiophene-2-carboxamide. Use according to claim 3, wherein the compound II is 3- (1-methylethoxy) -5-hydroxy-N-1H-tetrazol-5-yl-benzo [b] thiophene-2-carboxamide. 30 Use according to claim 3, wherein the compound is 5-methoxy-3- (1-methylethoxy) -N-1H-tetrazol-5-yl-benzo [b] thiophene-2-carboxamide. Use according to claim 3, wherein the compound is 6-methoxy-3- (1-methylethoxy) -N-1H-tetrazol-5-yl-benzo [b] thiophene-2-carboxamide. I DK 175445 B1 I I 24 I Use according to claim 3, wherein the compound is 5,6-dimethoxy-3- (1-methylethoxy) -N-11H-tetrazol-5-yl-benzo [b] thiophene-2-carboxamide. IN Use according to claim 3, wherein the compound is 7-chloro-6-methoxy-3- (1- 11 methylethoxy) -N-1H-tetrazol-5-yl-benzo [b] thiophene-2-carboxamide. IN Use according to claim 3, wherein the compound is 6-benzyloxy-3- (1-methylethoxy) -N-LI-1H-tetrazol-5-yl-benzo [b] thiophene-2-carboxamide. I I 10 Use according to claim 3, wherein the compound is 6-phenoxy-3- (1-methylethoxy) -N-11H-tetrazol-5-yl-benzo [b] thiophene-2-carboxamide. IN Use according to claim 3, wherein the compound is 5-benzyloxy-3- (1-methylethoxy) -N-11H-tetrazol-5-yl-benzo [b] thiophene-2-carboxamide. I I 15 I Use according to claim 3, wherein the compound is 5-phenoxy-3- (1-methylethoxy) -N-11H-tetrazol-5-yl-benzo [b] thiophene-2-carboxamide. IN Use according to claim 3, wherein the compound is 6-methoxy-3- (phenylmethoxy) -N-I-1H-tetrazol-5-yl-benzo [b] thiophene-2-carboxamide. IN Use according to claim 3, wherein the compound is 3-benzyloxy-5-methoxy-N-1H-1L tetrazol-5-yl-benzo [b] thiophene carboxamide. I I 25 I I I I I I 30 'I i i I I I I I