WO1993013776A1 - Use of paf antagonists in the treatment of dysmenorrhea - Google Patents

Abstract

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

Description

 Use of PAF antagonists to treat dysmenorrhea

The invention relates to the use of

 PAF antagonists, in particular PAF antagonists of hetrazepinoid structure for the treatment of

 Dysmenorrhea, especially the primary dysmenorrhea.

Various groups of drugs for the treatment of dysmenorrhea are known from the prior art (Red List 1991). On the one hand, non-hormonal antidysmenorrhoica are used therapeutically, such as analgesics and vitamin B ₆ complexes, and on the other hand, hormone-like medicines, such as ethinyl estradiol, are used to treat menstrual disorders. The use of analgesics indicates the well-known

 Side effects such as influencing responsiveness. Taking vitamin

B ₆ complexes only make sense if there is actually a lack of vitamin B ₆ . Sex hormones can also have a number of side effects, including:

Breast secretion and enlargement, rash,

Eryhtema nodosum, amenorrhea and an aggravation of endometriosis. On the other hand, have also been used to treat menstrual disorders

Prostaglandin synthesis inhibitor or cyclooxygenase inhibitor proposed; the disadvantages of such active substances - in particular the occurrence of gastric and intestinal ulcers are well known. With all these preparations, the effect, especially with heavy forms, is

Dysmenorrhea, often not fully satisfactory.

It was the object of the present invention

Medicines to treat dysmenorrhea,

especially the primary dysmenorrhea. Another task was to provide a drug for treatment with fewer side effects. This task is accomplished by using

 PAF antagonists, in particular solved by PAF antagonists of hetrazepinoid structure.

This task is accomplished by using

 PAF antagonists resolved in the treatment of dysmenorrhea, especially primary dysmenorrhea.

Compounds that are used as PAF antagonists (PAF = platelet activating factor) are in the

 Patent literature and the specialist literature known, e.g. in Prostaglandins 35, 781 (1988) or also in Handbook of PAF and PAF-Antagonists, Pierre Braguest, 1991 by CRC Press, Inc.

Known PAF antagonists are, for example, L-668750, LG-30435, MK-287, UK 74.505, Y 20411, Y24180,

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, Dilthiazem, 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, Seh - 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.

PAF antagonists are also of interest

hetrazepinoid structure, such as B. substituted

Hetrazepines of the general formula I

Roger that. They are known from the prior art, e.g. from European patent applications

EP-A-0.176.927, EP-A-0.176, 928, EP-A-0.176.929,

EP-A-0.194.416, EP-A-0.230.942, EP-A-0.240.899,

EP-A-0.254.245, EP-A-0.255.028, EP-A-0.268.242,

EP-A-0.279.681, EP-A-0.284.359, EP-A-0.291.594,

EP-A-0.298.466, EP-A-0.315.698, EP-A-0.320.992,

EP-A-0.342.456, EP-A-0.338 992, EP-A-0.328.924,

EP-A-0.342.587, EP-A-0.338 993, EP-A-0.367.110,

EP-A-O.368.175, EP-A-O.387.613, EP-A-0.407.955,

and the European patent application with the

Case number 91 114 518 and also from German published documents DE 40 10 361, 40 10 316,

40 15 137, to which reference is hereby made, in particular to those mentioned as preferred and particularly preferred in these documents

Embodiments.

Hetrazepines of the general formula are of particular interest ,

wherein

R _{1 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;

R _{2 is} a radical of the formula

worin A eine verzweigte oder unverzweigte

where A is 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

R ₆ and R ₇ , which can be the same or different,

Hydrogen, phenyl, substituted phenyl, an optionally substituted cycloalkyl group with 3 to 6 carbon atoms, a branched or unbranched alkyl, alkenyl or alkynyl group with 1 to 10 - preferably 1-4 - carbon atoms, optionally substituted by halogen, hydroxy, nitro, phenyl , substituted phenyl, amino, substituted amino, C ₁ to C ₈ - preferably C ₁ to C ₄ -alkoxy may be substituted;

R ₆ or R _{7 is} a saturated or unsaturated 5-, 6- or 7-membered heterocyclic ring optionally substituted one or more times by branched or unbranched alkyl having 1 to 4 carbon atoms, bonded via a carbon atom or nitrogen; or

R ₆ and R ₇ together with the nitrogen atom

saturated or unsaturated, optionally one or more times through branched or unbranched

Alkyl groups with 1 to 4 carbon atoms

substituted 5-, 6- or 7-ring, which may contain nitrogen, oxygen or sulfur as further heteroatoms, where each further nitrogen atom may be substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl; R ₈ phenyl, substituted phenyl;

R _{9 is} hydrogen, C ₁ to C ₄ alkyl;

R _{3 is} hydrogen, C ₁ -C ₄ alkyl

R _{4 is} phenyl, where the phenyl ring can be substituted one or more times, preferably halogen, nitro and / or trifluoromethyl;

R _{5 is} hydrogen, hydroxy, C ₁ -C ₄ -alkyl,

 preferably methyl, optionally substituted by hydroxy or halogen

 or

R ₂ and R ₃ together form a fused-on five- or six-membered ring of the formula

worin A, R₆, R₇, R₈ und R₉ die zuvor genannte wherein Ra is a radical of the formula

wherein A, R ₆ , R ₇ , R ₈ and R _{9 are} the aforementioned

 Have meaning and

R _{10 is} C ₁ -C ₄ alkyl or cyclopropyl,

R _{4 is} phenyl, where the phenyl ring can be substituted one or more times, preferably halogen, nitro and / or trifluoromethyl;

R _{5 is} hydrogen, hydroxy, C ₁ -C ₄ alkyl, preferably methyl, optionally substituted by hydroxy or halogen

and X can be nitrogen or CH.

Preferred compounds of the general formula 1 are those in which R ₁ = methyl

R ₂ = -CH ₂ -CH ₂ -CONR ₆ R ₇

R ₂ = -CH ₂ -CH ₂ -NR ₆ R ₇

R ₂ = -CH ₂ -CH ₂ iso-butyl;

R ₃ = hydrogen, R ₅ = methyl

R ₂ and R ₃ together

With

Ra = CONR ₆ R ₇

R ₆ / R ₇ = C ₃ H ₇ is particularly preferred

 or one together with the nitrogen atom

 Morpholino residue mean.

R ₅ = hydrogen, or methyl

R ₄ = ortho chlorophenyl.

Examples of alkyl groups (also insofar as they are part of other radicals) are: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.

Butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl and decanyl. Alkenyl groups are, for example, the alkyl groups mentioned above, provided that they have at least one double bond, such as vinyl (if no unstable enamines are formed), propenyl, isopropenyl, butenyl, pentenyl, hexenyl.

 Alkynyl groups are, for example, alkyl groups mentioned above, provided that they have at least one triple bond, such as, for example, propargyl, butynyl, pentynyl, hexynyl.

 Cycloalkyl radicals having 3 to 6 carbon atoms are, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which can be substituted by branched or unbranched alkyl having 1 to 4 carbon atoms, hydroxy, and / or halogen.

Examples of substituted phenyl are:

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-dimthoxyphenyl,

3,4,5-trimethoxyphenyl,

2-chlorobenzyl, 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 esters are:

Pyrrole, pyrroline, pyrrolidine, 2-methylpyrrolidine, 3-methylpyrrolidine, piperidine - optionally substituted one or more times by C ₁ - C ₄ alkyl - piperazine, N-methylpiperazine, N-ethylpiperazine,

 N-N-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 - being said

 Heterocycles can be substituted by alkyl with 1 to 4 carbon atoms - preferably methyl;

Examples of heterocyclic radicals which can be linked via a carbon atom are thiophene, 2-methylthiophene, furan, tetrahydrofuran,

 2-methyltetrahydrofuran, tetrahydrofuan,

 2-hydroxymethylfuran, α-pyran, γ-pyran,

 1,3-dioxolane, 1,2-oxathiolane, 1,2-oxathiepane,

Tetrahydro-pyran, thiolan, 1,3-dithiane, 1,3-dithiolane, 1,3-dithiols, the heterocycle by C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or halogen

can be substituted.

As a heterocycle within the scope of the previously specified

Definition generally also stands for a 5- to 6-membered ring which may contain oxygen, sulfur and / or nitrogen as heteroatoms, such as, for example, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyrazinyl, quinolyl, isoquinolyl, quinazolyl,

Quinoxalyl, thiozolyl, benzothiazolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl,

Benzimidazolyl, Pyrazolyl and Indolyl called. The PAF antagonists described above are suitable for use in accordance with the invention. The use of 4- (2-chlorophenyl) -9-methyl-2- [3 (4-morpholinyl) -3-propanon-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-l-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] -4H, 7H-cyclopenta [4,5] - thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazeρin

 (Web 2347) as well as that in the above

 Connections highlighted in Europe.

The compounds mentioned do not have the side effects known for analgesics. Although the

mentioned compounds to the chemical class of

Belonging to thieno-1,4-diazepines, it has been shown that they have no sedative properties.

Side effects like those with sex hormones or

Cyclooxygenase inhibitors can occur are not yet known and due to the different

chemical structures are also not to be expected.

The drug is expediently taken when the menstrual pain begins, as

It has also proven to be effective if you start taking it shortly before menstruation begins. If necessary, the intake can be repeated due to the good tolerance of the substances.

Surprisingly, it has been shown that the

Compounds proposed according to the invention can also be successfully used in particularly severe cases of primary dysmenorrhea ae. Using the example of 4- (2-chlorophenyl) -9-methyl-2- [3 (4-morpholinyl) -3-propanon-1-yl] -6H-thieno- [3,2-f] - [1,2 , 4] triazolo [4,3-a] [1,4] diazepines (I), after several months of application with an application of approximately 80 mg of substance, it was demonstrated that the intake of the compound quickly led to the complete disappearance of the menstrual pain . An effective oral single dose of the above-mentioned compound (I) is between 40 and 200 mg, preferably 80-150 mg,

 particularly preferably 90-120 mg. The single doses

 other PAF antagonists generally graded compared to this compound according to their relative PAF receptor binding affinities.

 Compounds with a higher receptor affinity than (I) are therefore generally more potent and in vivo

 require a lower therapeutic dose.

The compounds can be administered orally or parenterally

 Suppositories are administered. The compounds are active ingredients in the usual way

Dosage forms, e.g. in compositions consisting essentially of an inert pharmaceutical

Carrier and an effective dose of the active ingredient, e.g. Tablets, coated tablets, capsules,

Wafers, powders, solutions, suspensions, emulsions, syrups, suppositories, etc. In emergencies it would be conceivable to use the compounds in combination to be applied, the dosage then having to be correspondingly lower than in the case of oral application.

The connections mentioned are generally good

well tolerated and practically non-toxic

for example the substance 4- (2-chlorophenyl) -9-methyl-2- [3 (4-morpholine) -3-propananon-1-yl] -6H-thieno- [3,2-f] [1,2,4 ] - triazolo [4,3-a] [1,4] diazeρin an LD ₅₀ of 1960 mg / kg po, the substance 6- (2-chlorophenyl) -8,9-dihydro-1-methyl-8 - [( 4-morpholinyl) carbonyl] -4H, 7H-cycloρenta- [4,5] thieno- [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine an LD ₅₀ of 4600 mg / kg po.

The following examples serve to explain the invention in more detail.

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] diazepine-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-hydroxybenztriazole (HOBT) and 60 ml of absolute dimethylformamide are mixed with stirring at room temperature with 1.2 g (0.014 mol) of morpholine, giving a clear solution. At 0 - 5 ° C, 3.5 g of dicyclohexylcarbodiimide in solid form are then added over 5 to 10 hours and the temperature is maintained at 0 - 10 ° C for a further 6 - 8 hours. The fancy

 Dicyclohexylurea is filtered off, washed with a little cold dimethylformamide and the filtrate in

Evaporated vacuum. The residue is dissolved in

Methylene chloride, washes with 5% sodium carbonate solution and

Ice water, evaporate the organic phase and bring the residue in the ethyl acetate to crystallize.

Yield: 5.2 g (83.2% of theory) of colorless crystals,

Mp 189-190 ° C.

¹ H NMR (CDCl ₃ ), δ = 2.64 (2t, -CH -CO-), 2.71

(3s, CH ₃ ), 3.17 (2t, CH ₂ ), 3.33-3.81 (8m,

Morpholine), 4.96 (2s, CH ₂ ), 6.48 (ls, thiophene),

7.28-7.60 (4m, aryl) Example 1

Tablets containing 80 mg of substance

Composition:

Active ingredient 80.0 mg

 Cornstarch

 57.0 mg

 Milk sugar

 48.0 mg

 Polyvinyl pyrrolidone

 4.0 mg

 Magnesium stearate

 1.0 mg

 190.0 mg

Manufacturing process

The active ingredient, corn starch, milk sugar and

Polyvinyl pyrrolidone are mixed and moistened with water. The moist mixture is pressed through a sieve with a mesh size of 1.5 mm and dried at approx. 45 ° C. The dry granulate is passed through a sieve with a 1.0 mm mesh size and with

Magnesium stearate mixed. The finished mixture is pressed into tablets on a tablet press with stamps of 7 mm in diameter, which are provided with a partial notch.

Tablet weight: 190 mg Example 2

Dragees containing 50 mg of substance

Composition:

Active ingredient 50.0 mg

 Corn starch 41.5 mg

 Milk sugar 30.0 mg

 Polyvinyl pyrrolidone 3.0 mg

 Magnesium stearate 0.5 mg

 125.0 mg

Manufacturing process

The active ingredient, corn starch, milk sugar and

Polyvinyl pyrrolidone are mixed well and moistened with water. The moist mass is pressed through a sieve with a 1 mm mesh size, dried at approx. 45 ° C and then the granules are passed through the same sieve. After adding magnesium stearate, domed dragee cores with a diameter of 6 mm are pressed on a tablet machine. The dragee cores thus produced are coated in a known manner with a layer consisting essentially of sugar and talc. The finished coated tablets are polished with wax.

Drage weight: 175 mg Example 3

Tablets containing 50 mg of substance

Composition:

Active ingredient 50.0 mg

 Calcium phosphate 70.0 mg

 Milk sugar 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, milk sugar and

Corn starch is moistened evenly with an aqueous polyvinyl pyrrolidone solution. The mass is passed through a sieve with a mesh size of 2 mm

Circulating air drying cabinet dried at 50 ° C and sieved again. After the lubricant has been mixed in, the granules are pressed on a tabletting 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:

The substance and corn starch are mixed and moistened with water. The moist mass is sieved and

dried. The dry granules are sieved and mixed with magnesium stearate. The final mixture is filled into size 1 hard gelatin capsules.

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. The milled active substance is homogeneously dispersed at 40 ° C. It is cooled to 38 ° C and weakly pre-cooled

 Poured out suppository molds.

Example 6

Oral suspension containing 50 mg of substance per 5 ml

Composition:

Active ingredient 50 mg

 Hydroxyethylcellu Jose 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. Hydroxyethyl cellulose is dissolved therein with stirring. After adding sorbitol solution and glycerin, the mixture is cooled to room temperature. Sorbic acid, aroma and substance are added at room temperature. To vent the suspension, evacuate with stirring.

Claims

 Claims 1) Use of PAF antagonists to treat dysmenorrhea, especially primary ones  Dysmenorrhea. 2) Use of PAF antagonists of hetrazepinoid structure for the therapeutic treatment of  Dysmenorrhea, especially the primary one  Dysmenorrhea. 3) Use according to claim 1, or 2, characterized  characterized in that the PAF antagonist is a derivative of a thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine, 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] diazepines. 4) Use according to claims 1-3, characterized  characterized in that WEB 2086 or WEB 2170 is used as the PAF antagonist. 5) Use according to claim 1 or 2 thereby  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 in 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, Dilthiazem, 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, Seh - 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.