LU81352A1 - MEDICINE CONSISTING OF A CYCLOPENTYL-ADDEHYDE DERIVATIVE AND COMPOSITION CONTAINING THE SAME - Google Patents

Abstract

Cyclopentyl-aldehyde derivatives of the general formula <IMAGE> wherein X and Y, which can be the same or different represent CHO, CH2OH or COOH; Z represents a C1-C3 alkyl group; A represents -CH2-, <IMAGE> or <IMAGE> including their geometrical isomers are of value in therapy and may be formulated as therapeutical compositions.

Description

"% / R * Drug consisting of a cyclopentyl-aldehyde derivative and composition containing it.

The present invention relates to a new drug which consists of a derivative belonging to the family of cyclopenty1-aldehydes. The invention also relates to the therapeutic composition containing a cyclopentyl-aldehyde derivative as an active ingredient.

More precisely, the invention relates to a cyclopentyl-aldehyde derivative useful in therapy which is chosen from the group consisting of: a / the compounds of general formula

A-X

/ - \ (I) z 1 x in which X ßt Y, which may be identical or different, each represent CHO, CH ~ 0H or C00H; Z represents a C 1 -C 3 alkyl group; Represented-CH2 “, yC ^ Cï ^ or) CH (CH3); and, their geometric isomers.

The compounds of formula I are known substances which can be prepared either by synthesis or by extraction from a plant belonging to the Labiaceae family such as the species Teucrium marum, Teucrium polium and Teucrium montanum. For example,

They can be extracted from Teucrium marum according to the method described by PAGNONI et al. ” in Aust. J. Chem., (1976), 29, pages 1375-1381, article in which their pharmaceutical properties are not described. It has now surprisingly been found that the cyclopentyl aldehyde derivatives of formula I are (i) active as bacteriostatic, bactericidal, antispasmodic, antianaphylactic and anti-inflammatory agents, and (ii) useful in particular in the treatment of humans and warm-blooded animals suffering from infectious diseases caused by Gram (+) and Gram (-) germs, and allergies such as hay fever and asthma.

Furthermore, the cyclopentyl-aldehyde derivatives of formula I are more advantageous, from the pharmaceutical point of view, than the extracts of Teucrium marum according to US Pat. No. 4,151,278.

Among the compounds included in the definition of formula I, mention may in particular be made of the following compounds: Example 1: cK "(2-formyl-3-methyl-cyclopentyl) -acetaldehyde 20 (X". Y = CH0; A »CH2; Z» CH3), “Ex '. 2: 2 - (2-hydroxymethy 1-3-methyl-cydopentyl) -ethanol (X - Y - CH20; A = CH2; Z CH3)," Ex, 3: acid ° C- (2-carboxy-3-methyl-cyclopentyl) -acetic (X "Y - COOH; A" CH2; Z - CHg), 25 - Ex. 4 - (2-formyl-3-methyl-cyclopentyl) -acrylaldehyde (X "Y = CHO; A = ^> C" CH2; Z = CH3), "Ex" 5: 2- (2-hydroxymethyl-3-methyl-cyclopentyl) -2-propene-1 -ο 1 ( X - Y - CH2OH; AC "CH2; Z = CHg)," Ex. 6 îo (- (2-carboxy-3-methyl-cyclopentyl) -acrylic acid (X * Y COOH; A * / C "CH2; Z = CHg), and - Ex. 7: 2- (2-hydroxymethyl-3-methyl-cyclopentyl) -propan-1-ol / X = Y - CH20HI A = -CH (CH3); Z "chJ7, which correspond all â * the following formula: i "% '' 4" 3

- X

T di)) -k. h36 x (in which A and X are defined as above) and mainly have two isomers:

'A-X A-X

*. ^ k — k

5H, C X H.C X

(A) · 3 (B) "cis-trans" "trans-cis" the "cis-trans" isomer generally being more active than the "trans ~ cis" isomer.

The preferred compounds are those of Examples 1 and 4. The most interesting, from the pharmaceutical point of view, is the compound of Example 4.

The preferred mode for preparing the "acrylic" compounds (where A is "CHj) is to extract ° C *" (2-formyl-3-methyl-cyclopentyl) -acrylaldehyde from a species of Teucrium such as Teucrium marum,

Teucrium polium, Teucrium montanum, on the one hand, and to transform CHO into Cl ^ OH by reduction or into COOH by oxidation, on the other hand. The compounds in which A is (CHCH) (such as the product of Example 7) are obtained by catalytic hydrogenation. The compounds in which A is CI ^ are prepared in particular by synthesis according to a method known per se.

PREPARATION I

Obtaining_of0 ^ _- ^ 2-formyl-3-methyl-cyclopentyl) -acryl-. aldehyde_fExample. 4) 25 121 ° g of Teucrium polium (whole plant) dried and ground are extracted in a column with k 4 β 9 successively 7.35 liters of hexane and 7.25 liters of chloroform. The chloroform extract is evaporated to dryness under vacuum and the residue thus obtained (45 g) is entrained in water vapor. The distillate is saturated with sodium chloride, then extracted with chloroform after drying over Na2SO4; the chloroform is removed by distillation under reduced pressure (0.3 mm Hg) to

give 7.3 g (0.6% yield) of a yellow oil 25 ° C

(n ^ j = 1.4842) including c ("ch2) -cho 10 89 Z by weight of * f>

H3C CHO

("cis-trans") is 11 Z by weight of / \ a \\ ^ g (, bCH2> 'CH0

H3C * V CHO

("trans-cis")

PREPARATION II

Q! Î £ 22 £ i'25-â224li? -F ormyl-3-méthy l-çyclo £ entyl ^ -acry 1-15 âlâ | kïde_ £ example 4) 25 kg of dried and ground Teucrium marum (planted) extracted by leaching in a glass column (height: 2 m; 0: 0.225 m) filled with solvent by means of a pump having a flow rate of 10 1 / h. Two sol-,

20 wings are used successively: hexane (170 liters) then chloroform (170 liters). The hexane extract is discarded. The chloroform extract is evaporated to dryness in vacuo to give a brown oily residue (640 g) which is vapor entrained. The distillate is saturated with NaCl 25 and then extracted with chloroform. The chloroform phase is dried over NaSO 4, the solvent is evaporated and the remaining oil is distilled (under 1 mm Hg at 60-78 ° C) to give A

4 * '. »5

25 ° C

42 g of a yellow oil (nQ 1.4842) which comprises: - 87% by weight of "cis-trans" isomer - 13% by weight of "trans-cis" isomer

PREPARATION III

Ob ten tion_de_2 - (2 “h ^ droxyme thYl ~ 3-mé thy1-cyclopenty1 5“ 2i_ (example 5)

By reduction of the "cis-trans" isomer of Example 4 (1.4 g) dissolved in CH ^ OH (25 ml) with NaBH ^ (1.7 g), the "cis-trans" isomer of Example 5 (1.19 g) is obtained in the form of an oil. According to the same technique, the "trans-cis" isomer of Example 5 is prepared from the "trans-cis" isomer of Example 4.

PREPARATION IV

Qk ££ E £ ï £ E_ée_2y £ 2yhydroxymethyl-3yméthylycycloEentyl) - £ r ££ an-l_- £] ___ ([example 7)

The “cis-trans” and “trans-cis” isomers of Example 7 are obtained by hydrogenation on PtO 3 of the corresponding isomers of the product of Example 5 according to the technique described by PAGNONI et al.

The pharmaceutical tests which were carried out with the products of Examples 1 and 4 were summarized below: 1 ° / tests with Example 1 a / bacteriostatic activity L'0 ^ - (2-formyl-3 -methyl-cyclopentyl) -acetaldehyde inhibits Gram (+) and Gram (-) bacteria. The MICs (minimum inhibitory concentration) are as follows: '0.75 mg / ml on Staphylococcus aureus London,> 1.2 mg / ml on Escherichia coli, and 1.5 mg / ml on Proteus%' · 6 b / antispasmodic activity:

The ED-50 of the product of Example 1 were determined (i) in vitro on an ileum isolated from guinea pig with respect to histamine: • DE - 50 = 50 Y / ml}.

(Ii) in vivo on the living animal according to the KONZETT & ROESLLER method: DE - 50 = 2.6 mg / kg by i .v administration.

c / anti-anaphylactic activity: I *

Male guinea pigs are sensitized by two injections of -0.5 ml of a 2 g / l albumin solution, two days apart. Four weeks later, the fatal anaphylactic shock is caused by i.v. injection of 0.2 ml of an aqueous solution of ovalbumin at 2 g / 1. The 15 products to be tested are administered 30 min before (i.p. administration) or at the same time (i.v. administration) as the injection causing said anaphylactic shock. The results are given in Table I for the product of Example 1 2o and 1 & Promethazine as a reference product:

TABLE I

Compound Mortality Protection (dose)%% controls 80% 20%

Promethazine 25 (20 mg / kg i.p.) 0 Z 100%

Example 1 (10 mg / kg i.p.) 50% 50%

Example 1 0 Z 100 Z

30 më / kg iv) l ♦ “7 2e / tests with the product of Example 4 (consisting of a mixture of 87 Z by weight of“ cis-trans ”isomer and 13 Z by weight of“ trans-isomer ” cis) .a / bacteriostatic activity: The product of Example 4 inhibits bacteria

Gram (+) and Gram (-). Its MICs are as follows: 1.5 mg / m on Staphylococcus aureus, London 1 mg / ml on Escherichia coli (strain 548) 1.75 mg / ml on Proteus vulgaris (strain 1557) 10 2.5 mg / ml on Klebsiella pneumoniae ( strain 433), „1 mg / ml on Salmonella typhi murium (strain IP), 1.5 mg / ml on Staphylococcus aureus (strain 634), 1.25 mg / ml on Streptococcus (strain 1178) 1.25 mg / ml on Bacillus substilis, 15 ( the strains 548, 1557, 433, 634, and 1178 being those of the catalog of the collection of the "International Center for the Distribution of Strains and Information on Mic.robian Types" from Lausanne, and the strain "IP" from • 20 the Institut Pasteur in Paris.

b / bactericidal activity

The product of Example 4 destroys the Gram (+) and Gram (-) bacteria. Its CMB (minimum bactericidal concentration) determined on solid medium (when less than 0.01% of germs survive) are: 1.75 mg / ml on Staphylococcus aureus London 1.5 mg / ml on Escherichia coli (strain 548) 2 mg / ml on Proteus vulgaris (strain 1557) 3 mg / ml on Klebsiella pneumoniae (strain 433), 3 ° 1.25 mg / ml on Salmonella typhi murium (strain IP) 1.75 mg / ml on Staphylococcus aureus (strain 634) 2 mg / ml on Streptococcus (strain 1178) 2.5 mg / ml on Bacillus substilis.

, "’ Ί [8 c / bronchospatic activity

Male or female guinea pigs in animals (weighing 300-500 g) per dose and per product to be tested are exposed to an aerosol of Example 4 (50 g / 1 5 in water-ethanol solution) or Promethazine (product of reference) for 10 min.

The animals are then individually exposed to a histamine aerosol (3 g / 1 of histamine in an aqueous medium containing 200 g / 1 of glycerin).

The criterion chosen is the time elapsed between the start of exposure to histamine and apnea, accompanied by the fall of the animal.

The control batch receives only the aerosol of histamine. The results are given in Table II and show that the product of Example 4 has a bronchodilator effect which is opposed to the bronchoconstrictor effect of histamine:

TABLE II

20 'Product Appearance of Variation (dose) apnea vis g vis (in seconds) witnesses Witnesses · 108 + 18

Promethazine y6Q0 - 0.1 mg / kg

Ex. 4 (1 mg / kg) 130 + 23 + + 20% 25 Ex 4 (10 mg / kg) 169 + 32 ♦ + 56%

Note: ♦ statistically significant (P ^ 0.05) 9

AT

"In vitro anti-anaphylactic activity

Male guinea pigs are sensitized by an i.p. 100 mg / kg ovalbumin in an equal volume of Freund's adjuvant. Four weeks later, the animals are sacrificed, each ileum is collected which is placed at 33 ° C. in a Thyrode bath. A contraction is caused by adding a dose of 20 ^ / U | g of albumin to the survival fluid. The amplitude of the contractions of the controls is compared to the amplitude of the contractions after bringing the product of Example 4 into contact for 2 min. The results # given in Table III show that the product of Example 4 reduces the amplitude of the contractions of the isolated guinea pig ileum, this reduction being statistically significant. in vitro

Guinea pigs (male or female) are sensitized to ovalbumin four weeks before the start of the experiment. Each animal is exposed. se to an aerosol of valbumin (obtained from an aqueous medium containing 50 g / l of ovalbumin). Anaphylactic shock is manifested by the appearance of intense dyspnea. The onset times of dyspnea are compared between control batch and batches previously treated with an aerosol of the product of Example 4 (50 g / 1 in a water-ethanol solution). The results given in Table IV show that the product of Example 4 • decreases the time of onset of respiratory disorders caused by the aerosol of ovalbumin.

—Fl 10

TABLE III

Product Number amplitude variation of the ampli- (dose) of anima-ux de3 study compared to control animal contractions * - - - —— - - - —— - - - - - - - —— - ^ «+ - - - V - - mm - "" ι · ιι · _ "- - _ —————— - witnesses 20 147 +32

Ex. 4

(5 / uyml) 20 91 + 37 * - 38 Z

Ex. 4

. 5 (10 / ¾ / ml) 20 52 + 16 * - 65 Z

Note *: statistically significant (p <0.05)

TABLE IV

Product Number Dyspnoea Variation in (dose) of animals time of appearance of appearance ^ rition (second compared to _____________________________ of ____________ controls _____ controls 20 94 + 39 10 Ex · 4

(1 mg / kg) 20 120 + 52 + 28 Z

Ex. 4

(10 mg / kg) 20 130 + 54 + 38 Z

11 * - '*' '1 ------! - -., 1.,., 1 - - I 11-, 1-.11, e / anti-inflammatory activity The anti-inflammatory activity of example 15 4 was studied in] The female rat (of weight 100 g) according to the carrageenan edema test. The results are given in Table IV where Indomethacin is used as reference product:

TABLE V

20 Product Number inhibition dose per animal (per rat) compared to controls

Ex. 4 10 1 ° 26%

* - -_____ - I

'1 i 1 1 TABLE V (continued)

Product Number inhibition dose per animal (per rat) compared to controls

Ex. 4 10 50 ^ 25%

Ex. 4 10 20041 Z

Indomethacin 10,200 ^ ug 57%

^ '1! - i. . i. . ... 1 1 1 "1 I

511 Antispasmodic Activity The antispasmodic activity of the product of Example 4 was studied on the duodemone isolated from rats with respect to acetylcholine and barium chloride ··. The ED-50 of the product of Example 4 are: 10 (i) 13 ^ ug / ml with respect to acetycholine (0.2 yttg / ml) ^ and (ii) 10 ^ ug / ml with respect to of BaC ^ (0.3 yU / g / ml). g / toxicity

The DL-50 ^ u weight of Example 4 in mice are as follows: 15 DL ~ 50 i.p. = 18 + 3 mg / kg DL-50 i.v. = 20 +3 mg / kg LD ~ 50 p.o. = 282 £ 3 mg / kg DL ”50 s.c.> 1000 mg / kg“ PL “50 aerosol = 2? + 3 mg / kg 20 According to the invention, a therapeutic composition is recommended comprising, in association with a physiologically acceptable excipient, a pharmaceutically effective amount of a cyclopenty1-aldehyde derivative of formula I.

Such a composition can be administered orally in the form of tablets, dragees, syrup and buyable ampoules, by injection and in the form of an aerosol. 1,112

According to the preferred embodiment of the invention, the compound of Example 4 or its "cis-trans" isomer, preferably 5 in the form of an aerosol, is administered to humans and warm-blooded animals. (in solution in carbitol or in suspension in freon or a freon-alcohol mixture).

Advantageously, the aerosol composition will contain 0.1 to 10% of the product of Example 4 or of its "cis-trans" isomer.

The product of Example 4 and its "cis-trans" isomer can also be administered orally * in the form of soft capsules (the active ingredient being in oily solution), of 15 capsules (the active ingredient being combined è a viscous or solid excipient), the preferred excipient for the capsules being in particular a mixture of oleic-polyoxyethylene glycerides obtained by alcoholysis of natural vegetable oil and which are sold under the name LABRAFIL.

Claims (6)

1. Medicinal product useful in therapy in the treatment of infectious diseases, pain, inflammation and allergies, in particular hay fever, consisting of a cyclopentyl-aldehyde derivative 5 characterized in that the active ingredient is chosen from the group consisting of: a / cyclopentyl-aldehyde derivatives of general formula A_X ZN ^ (I) in which X and Y, identical or different, each represent CHO, CK ^ OH or COOH; £ represents a C 1 -C 10 alkyl group; A represents -CH ^ "·, = C ^ and ^ CH (CHg); and b / their geometric isomers. 2. Medicament according to claim 1 characterized in that X = Y »CHO, C ^ OH and Z» CHg. 3. Medicament according to claim 1 characterized in that the geometric isomer is chosen from the group consisting of: a / the "cis-trajis" isomers of formula: jAj * Ax H3C * "\ and," b / "trans-cis" isomers of formula: "Λ * '14 ^ A - XA H3C X or A and X are defined as above. 4. Medicament according to claim 3 characterized in that X is CHO, Z is CH ^ and A is ^ C = CH2 · 5. Therapeutic composition characterized in that it contains, in association with a physiologically acceptable excipient, a pharmacologically active amount of a cyclopentyl-aldehyde derivative of formula X or one of its geometric isomers. 6. Therapeutic composition according to claim 5 characterized in that the cyclopentyl-aldehyde derivative is l * ° ^ - (2-f ormyl-3-methyl-cyclopentyl) -acrylaldehyde. \ t * "