DE4200610A1 - USE OF PAF ANTAGONISTS FOR THE TREATMENT OF DYSMENORRHEA - Google Patents

Abstract

The invention concerns the use of platelet activation factor antagonists to dysmenorrhea.

Description

The invention relates to the use of PAF antagonists, especially PAF antagonists hetrazepinoid structure for the treatment of Dysmenorrhea, especially the primary dysmenorrhea.

The prior art includes various groups of Medicines known for the treatment of dysmenorrhea (Red List 1991). First, non-hormonal Antidysmenorrhoics therapeutically applied, such. B. Analgesics and vitamin B₆ complexes, for another hormonal drugs, such as. Ethinyl estradiol, for Treatment of menstrual disorders in the trade. The Ingestion of analgesics has the well-known Side effects such. B. the influence of the Responsiveness. The intake of vitamin B₆ complexes are only useful if actually a lack of vitamin B₆ is present. The Sex hormones can also be taken with one Range of side effects, such as B. Breast secretion and enlargement, rash, Eryhtema nodosum, amenorrhoea and a reinforcement from endometriosis. On the other hand were used for treatment of menstrual disorders also already Prostaglandinsynthesehemmer or Cyclooxygenasehemmer proposed; the disadvantages of such agents - especially the occurrence of gastric and intestinal ulcers - are well known. For all these preparations is the effect, especially in severe forms of Dysmenorrhea, often not fully satisfactory.

It was the object of the present invention, a Medicines for the treatment of dysmenorrhea, especially the primary dysmenorrhea, available too put. It was another task a drug available for treatment with fewer side effects deliver.  

This task is accomplished through the use of PAF antagonists, especially PAF antagonists hetrazepinoider structure solved.

This task is accomplished through the use of PAF antagonists in the treatment of dysmenorrhea, especially the primary dysmenorrhea resolved.

Compounds known as PAF antagonists (PAF = platelet activating factor) are used in the Patent literature and the subject-specific literature known, such. In prostaglandins 35, 781 (1988) or also in Handbook of PAF and PAF antagonists, Pierre Braquest, 1991 by CRC Press, Inc.

Known PAF antagonists are, for example, L-668 750, LG-30 435, MK-287, UK 74 505, Y 20 411, Y 24 180, RO 244 736, E 6123, CV 6209, Alprazolam, BN-50 730, BN-50 727, BN-50 766, BN-54 068, BN-50 739, BN-50 726, BN-52 022, BN-52 021, BN-52 020, BN-52,025, BN-52,115, BN-52,111, BN-52,023, BN-52 024, BN-50 580, BN-50 585, Brotizolam, CV 6209, CN-3988, dilithiazem, E-6123, E-5880, F-1850, FR-49 175, FR-90 0452, FR-10 6969, Kadsurenon, L-653 150, L-668 750, L-652 731, L-659 989, LG-50 643, MK-287, ONO-6240, PCA-4248, R-74 654, RN-70 727, RO-244 736, RO-19 3704, RP-55 778, RP-59 227, RP-55 270, RP-48 740, RP-52 770, RU-45 703, Sch-37 370, SDZ-64 412, SM-10 661, SRI-63 675, SRI-441, SRI-63 119, SRI-63,072, TCV-309, triazolam, UK-74 505, UR-10 324, UR-11 353, Y-24 180, Y-20 411, YM-461, YM 264.

Also of interest are PAF antagonists hetrazepinoider structure, such. B. substituted Hetrazepines of general formula I

Roger that. They are known from the prior art, so z. B. from the European patent applications EP-A-01 76 927, EP-A-01 76 928, EP-A-01 76 929, EP-A-01 94 416, EP-A-02 30 942, EP-A-02 40 899, EP-A-02 54 245, EP-A-02 55 028, EP-A-02 68 242, EP-A-02 79 681, EP-A-02 84 359, EP-A-02 91 594, EP-A-02 98 466, EP-A-03 15 698, EP-A-03 20 992, EP-A-03 42 456, EP-A-03 38 992, EP-A-03 28 924, EP-A-03 42 587, EP-A-03 38 993, EP-A-03 67 110, EP-A-03 68 175, EP-A-03 87 613, EP-A-04 07 955, as well as the European patent application with the File number 9 11 14 518 and also from the German Laid-open publications DE 40 10 361, 40 10 316, 40 15 137, incorporated herein by reference is, in particular to those in these writings as preferred and particularly preferred mentioned Embodiments.

Of particular interest here are hetrazepines of general formula

wherein
R₁ is hydrogen, a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl, which may optionally be substituted by hydroxy or halogen, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, halogen, preferably chlorine and bromine;
R₂ is a radical of the formula

wherein
A is a branched or unbranched alkyl group with n carbon atoms, where n is one of the numbers 0, 1, 2, 3, 4, 5, 6, 7 or 8;
R₆ and R₇, which may be the same or different, are hydrogen, phenyl, substituted phenyl, an optionally substituted cycloalkyl group having from 3 to 6 carbon atoms, a branched or unbranched alkyl, alkenyl or alkynyl group having from 1 to 10, preferably 1 to 4 carbon atoms, optionally substituted by halogen, hydroxy, nitro, phenyl, substituted phenyl, amino, substituted amino, C₁- to C₈-, preferably C₁- to C₄-alkoxy may be substituted;
R₆ or R₇ represents a mono- or polysubstituted by branched or unbranched alkyl having 1 to 4 carbon atoms, saturated or unsaturated bonded via a carbon atom or nitrogen 5-, 6- or 7-membered heterocyclic ring; or
R₆ and R₇ together with the nitrogen atom, a saturated or unsaturated optionally mono- or polysubstituted by branched or unbranched alkyl groups having 1 to 4 carbon atoms substituted 5-, 6- or 7-ring, which may contain as further heteroatoms nitrogen, oxygen or sulfur, wherein each additional nitrogen atom may be substituted by a branched or unbranched alkyl group having from 1 to 4 carbon atoms, preferably methyl;
R₈ is phenyl, substituted phenyl;
R₉ is hydrogen, C₁ to C₄ alkyl;
R₃ is hydrogen, C₁-C₄alkyl;
R₄ is phenyl, where the phenyl ring may be monosubstituted or polysubstituted, preferably halogen, nitro and / or trifluoromethyl;
R₅ is hydrogen, hydroxy, C₁-C₄-alkyl, preferably methyl, optionally substituted by hydroxy or halogen or
R₂ and R₃ together form a fused five- or six-membered ring of the formula

wherein R _{a is} a radical of the formula

wherein A, R₆, R₇, R₈ and R₉ have the abovementioned meaning and
R₁₀ is C₁-C₄ alkyl or cyclopropyl,
R₄ is phenyl, where the phenyl ring may be monosubstituted or polysubstituted, preferably halogen, nitro and / or trifluoromethyl;
R₅ is hydrogen, hydroxy, C₁-C₄-alkyl, preferably methyl, optionally substituted by hydroxy or halogen means and
X can mean nitrogen or CH.

Preference is given to those compounds of the general formula 1 in which
R₁ = methyl
R₂ = -CH₂-CH₂-CONR₆R₇
R₂ = -CH₂-CH₂-NR₆R₇

R₃ = hydrogen, R₅ = methyl
R₂ and R₃ together

With
Ra = CONR₆R₇,
particularly preferably R₆ / R₇ = C₃H₇ or together with the nitrogen atom signify a morpholino radical,
R₅ = hydrogen, or methyl,
R₄ = ortho-chlorophenyl.

As alkyl groups (even if they are part of another Radicals are) are for example called: methyl, Ethyl, propyl, iso-propyl, butyl, iso-butyl, sec. Butyl, tert-butyl, pentyl, iso-pentyl, hexyl, heptyl, Octyl, nonyl and decanoyl.  

As alkenyl groups, for example, the above Alkyl groups, if they have at least one Have double bond, such as vinyl (so far no fugitive enamines are formed), propenyl, iso-propenyl, butenyl, pentenyl, hexenyl.

As alkynyl groups, for example, the above Alkyl groups, if they have at least one Have triple bonds, such as propargyl, Butynyl, pentynyl, hexynyl.

As cycloalkyl radicals having 3-6 carbon atoms for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which is characterized by branched or unbranched alkyl having 1 to 4 carbon atoms, Hydroxy and / or halogen may be substituted.

Examples of substituted phenyl are mentioned:
3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 4-fluoromethylphenyl, 2-chlorophenyl, 2-bromophenyl, 3-fluorophenyl, 2,3-dichlorophenyl, 2-methylphenyl, 4-methylphenyl, 3-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl, 4-tert-butylphenyl, 4-iso-butylphenyl, 4-pentylphenyl, 2,4-dimethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl , 4-methoxyphenyl, 3-ethoxyphenyl, 2-propoxyphenyl, 4-butoxyphenyl, 2,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-chlorophenyl, 2,3-dichlorobenzyl, 2-methylbenzyl, 2-trifluoromethylbenzyl, 4 Methoxybenzyl, 3,4,5-trimethoxybenzyl, 2- (2-chlorophenyl) ethyl.

Examples of optionally substituted saturated or unsaturated heterocyclic 5, 6 or 7-membered rings or heteroaryl radicals are:
Pyrrole, pyrroline, pyrrolidine, 2-methylpyrrolidine, 3-methylpyrrolidine, piperidine - optionally mono- or polysubstituted by C₁-C₄alkyl - piperazine, N-methylpiperazine, N-ethylpiperazine, NN-propylpiperazine, N-benzylpiperazine, morpholine, thiomorpholine , Imidazole, imidazoline, imidazolidine, triazole, pyrazole, pyrazoline, pyrazolidine, triazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, 1,2,4,5-tetrazine - the said Heterocycles by alkyl having 1 to 4 carbon atoms - preferably methyl - may be substituted.

As heterocyclic radicals, which have one carbon atom For example, thiophene, 2-methylthiophene, furan, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydrofuran, 2-hydroxymethylfuran, α-pyran, γ-pyran, 1,3-dioxolane, 1,2-oxathiolane, 1,2-oxathiepan, Tetrahydro-pyran, thiolane, 1,3-dithiane, 1,3-dithiolane, 1,3-dithiols, called, wherein the heterocycle by C₁-C₄alkyl, C₁-C₄alkoxy or halogen may be substituted.

As a heterocycle within the scope of the above Definition also generally stands for a 5- to 6-membered ring which, as heteroatoms, oxygen, May contain sulfur and / or nitrogen, such as Example, thienyl, furyl, pyridyl, pyrimidyl, Pyrazinyl, quinolyl, isoquinolyl, quinazolyl, Quinoxalyl, thiozolyl, benzothiazolyl, isothiazolyl, Oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, Benzimidazolyl, pyrazolyl and indolyl.  

The PAF antagonists described above are suitable for the application according to the invention. To emphasize is the use of 4- (2-chlorophenyl) -9-methyl-2- [3 (4-morpholinyl) -3-propanone-1-yl] -6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine (WEB 2086); 6- (2-chlorophenyl) -8,9-dihydro-1-methyl-8 - [(4-morpholinyl) carbonyl] - 4H, 7H-cyclopenta [4,5] thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine (Web 2170) or the 6- (2-chlorophenyl) -8,9-dihydro-1-methyl-8- [Dipropylaminocarbonyl] -4, 7H-cyclopenta [4,5] - thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine (Web 2347) as well as in the above European applications highlighted links.

The compounds mentioned have the analgesics not known side effects. Although the said compounds of the chemical class of Belong to Thieno-1,4-diazepine, it has been demonstrated that they have no sedative properties. Side effects, as with sex hormones or Cyclooxygenase inhibitors may occur so far not known and due to the different chemical structures are also not expected.

The ingestion of the medicament is expediently carried out at the onset of menstrual pain, as It has also proved effective when with the Ingestion started just before the onset of menstruation becomes. If necessary, the intake due to good compatibility of the substances are repeated.

Surprisingly, it has been shown that the Compounds proposed according to the invention also in particularly severe cases of primary dysmenorrhea can be successfully applied.  

The example of 4- (2-chlorophenyl) -9-methyl-2- [3 (4- morpholinyl) -3-propanone-1-yl] -6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine (I) was in a several months of use with an application of approx. 80 mg substance provided evidence of ingestion the connection quickly disappears completely Menstrual pain resulted. An effective oral Single dose of the above compound (I) is between 40 and 200 mg, preferably 80-150 mg, more preferably 90-120 mg. The single doses Other PAF antagonists are generally classified as Comparison to this compound according to her relative PAF receptor binding affinities. Compounds with a higher receptor affinity than (I) are therefore more potent in vivo and in vivo require a lower therapeutic dose.

The compounds may be administered orally or parenterally Suppositories are administered. The connections are here as active ingredients in usual Dosage forms before, z. In compositions that essentially from an inert pharmaceutical Carrier and an effective dose of the active ingredient exist, such. As tablets, dragees, capsules, Wafers, powders, solutions, suspensions, emulsions, Syrups, suppositories, etc. In emergencies, it would be conceivable the compounds also i.V. to apply, with the Dosage then correspondingly lower than in oral Application must be made.

The compounds mentioned are usually good tolerable and practically non-toxic, so points for example, the substance  4- (2-chlorophenyl) -9-methyl-2- [3 (4-morpholinyl) - 3-propanone-1-yl] -6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine an LD₅₀ of 1960 mg / kg p. o., the substance 6- (2-chlorophenyl) -8,9-dihydro-1 methyl-8 - [(4-morpholinyl) carbonyl] -4H, 7H-cyclopenta [4,5] thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine an LD₅₀ of 4600 mg / kg p.o. on.  

The following examples are given for further explanation the invention.

Production of the active ingredients using the example of 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] -ethane-1-carboxylic acid morpholide

5.3 g (0.014 mol) of 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,4] diazepin-2-yl] -ethane-1 carboxylic acid, 1.8 g of N-hydroxybenzotriazole (HOBT) and 60 ml of absolute dimethylformamide are added with stirring at room temperature with 1.2 g (0.014 mol) of morpholine, with a clear solution. At 0-5 ° C is then added over 5 to 10 hours 3.5 g of dicyclohexylcarbodiimide in solid form and the temperature for a further 6-8 hours at 0-10 ° C. The precipitated dicyclohexylurea is filtered off, washed with a little cold dimethylformamide and the filtrate evaporated in vacuo. The residue is dissolved in methylene chloride, washed with 5% sodium carbonate solution and ice-water, the organic phase is evaporated and the residue is crystallized in ethyl acetate.
Yield: 5.2 g (83.2% of theory) of colorless crystals, mp 189-190 ° C.
¹H-NMR (CDCl₃), δ = 2.64 (2t, -CH₂-CO-), 2.71 (3s, CH₃), 3.17 (2t, CH₂), 3.33-3.81 (8m, Morpholine), 4.96 (2s, CH₂), 6.48 (1s, thiophene), 7.28-7.60 (4m, aryl).

example 1 Tablets containing 80 mg of substance

composition Active ingredient | 80.0 mg corn starch 57.0 mg lactose 48.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate  1.0 mg 190.0 mg

production method

The active ingredient, corn starch, lactose and polyvinylpyrrolidone are mixed and moistened with water. The moist mixture is forced through a sieve of 1.5 mm mesh size and dried at about 45 ° C. The dry granules are beaten through a 1.0 mm mesh screen and mixed with magnesium stearate. The finished mixture is compressed on a tablet press with punches of 7 mm diameter, which are provided with a partial notch, into tablets.
Tablet weight: 190 mg

Example 2 Drag'es containing 50 mg of substance

composition Active ingredient | 50.0 mg corn starch 41.5 mg lactose 30.0 mg polyvinylpyrrolidone 3.0 mg magnesium stearate  0.5 mg 125.0 mg

production method

The active ingredient, corn starch, lactose and polyvinylpyrrolidone are mixed well and moistened with water. The moist mass is forced through a sieve with 1 mm mesh size, dried at about 45 ° C and then strikes the granules through the same sieve. After admixing magnesium stearate, corrugated drag cores having a diameter of 6 mm are pressed on a tableting machine. The Drag'ekerne thus prepared are coated in a known manner with a layer consisting essentially of sugar and talc. The finished Drag'es are polished with wax.
Drag'e weight: 1175 mg

Example 3 Tablets containing 50 mg of substance

composition Active ingredient | 50.0 mg calcium phosphate 70.0 mg lactose 40.0 mg corn starch 35.0 mg polyvinylpyrrolidone 3.5 mg magnesium stearate  1.5 mg 200.0 mg

manufacturing

The substance, calcium phosphate, lactose and Corn starch are mixed with an aqueous solution of polyvinylpyrrolidone evenly moistened. The crowd will through a sieve with 2 mm mesh size, in Drying cabinet dried at 50 ° C and again sieved. After admixing the lubricant is the Granules pressed on a tableting machine.  

Example 4 Capsules containing 50 mg of substance

composition Active ingredient | 50.0 mg corn starch 268.5 mg magnesium stearate  1.5 mg 320.0 mg

manufacturing

Substance and cornstarch are mixed and mixed with water moistened. The moist mass is sieved and dried. The dry granules are sieved and washed with Magnesium stearate mixed. The final mixture is in Hard gelatine capsules size 1 bottled.

Example 5 Suppositories containing 50 mg of substance

composition Active ingredient | 50 mg Adeps solidus 1 650 mg 1 700 mg

manufacturing

The hard fat is melted. At 40 ° C, the milled active substance dispersed homogeneously. It will open Cooled to 38 ° C and slightly pre-cooled Suppository forms poured out.

Example 6 Oral suspension containing 580 mg of substance per 5 ml

composition Active ingredient | 50 mg hydroxyethyl 50 mg sorbic acid 5 mg Sorbitol 70% 600 mg glycerin 200 mg Aroma 15 mg Water ad 5 ml

manufacturing

Distilled water is heated to 70 ° C. This is where dissolved with stirring hydroxyethyl cellulose. After adding of sorbitol solution and glycerin is brought to room temperature cooled. At room temperature, sorbic acid, flavor and substance added. For venting the suspension is evacuated with stirring.

Claims (6)

1. Use of PAF antagonists for the treatment of Dysmenorrhea, especially the primary Dysmenorrhea. 2. Use of PAF antagonists hetrazepinoider Structure for the therapeutic treatment of Dysmenorrhea, especially the primary Dysmenorrhea. 3. Use according to claim 1 or 2, characterized characterized in that the PAF antagonist is a derivative a thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine, of a cyclopenta [4,5] thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine or a 2,3,4,5-tetrahydro-8H-pyrido- [4 ', 3': 4,5] thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine is. 4. Use according to claims 1-3, characterized characterized in that as PAF antagonist WEB 2086 or WEB 2170 is used. 5. Use according to claim 1 or 2, characterized characterized in that as PAF antagonist Y 20 411, Y 24 180 RO 24 4736, E 6123, BN 50 730, BN 50 739 or BN 50 726 is used.   6. Use according to claim 1, characterized that as PAF antagonist alprazolam, BN-50 730, BN-50 727, BN-50 766, BN-54 068, BN-50 739, BN-50 726, BN-52 022, BN-52 021, BN-52 020, BN-52,025, BN-52,115, BN-52,111, BN-52,023, BN-52 024, BN-50 580, BN-50 585, Brotizolam, CV 6209, CN-3988, dilithiazem, E-6123, E-5880, F-1850, FR-49 175, FR-90 0452, FR-10 6969, Kadsurenon, L-653 150, L-668 750, L-652 731, L-659 989, LG-50 643, MK-287, ONO-6240, PCA-4248, R-74 654, RN-70 727, RO-244 736, RO-19 3704, RP-55 778, RP-59 227, RP-55 270, RP-48 740, RP-52 770, RU-45 703, Sch-37 370, SDZ-64 412, SM-10 661, SRI-63 675, SRI-441, SRI-63 119, SRI-63,072, TCV-309, triazolam, UK-74,505, UR-10 324, UR-11 353, Y-24 180, Y-20 411, YM-461, YM 264 is used.