Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/44—Nitrogen atoms not forming part of a nitro radical
  • C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/10—Drugs for disorders of the urinary system of the bladder
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to m-aminophenylimino-imidazolidine derivatives with a new substituent pattern on the phenyl ring and to the use of m-aminophenylimino-imidazolidine derivatives for the production of medicaments, in particular for the treatment of urinary incontinence and the production process thereof.
• the compounds described in the context of the present invention belong to the class of m-amino-phenylimino-imidazolidines. Similar compounds are known from the prior art.
• EP-A-0 236 636 inter alia m-amino-phenylimino-imidazolidine derivatives, with a primary amino function in the 3-position and their use as hemostatic agents.
• Such clonidine derivatives are also described in EP-A-0 070 084, EP-A-0081923, EP-A-0117102, EP-A-0 149 140, DE-A-2806811 or DE-A -2854659 treated.
• US-A-4587257 and EP-A-0081924 disclose m-aminophenyliminoimidazolidine derivatives with primary or acetylated amino function which can be used in ophthalmology.
• Biochem. Pharmacol. 32 (12) (1983) 1933-1940 discloses in a different context, among other things, 2- (3-amino-2,6-dichlorophenylimino) imidazolidine.
• US-A-4287201 describes, for example, 2- (3-diethylamino-2-methylphenylimino) imidazolidine for increasing the egg production.
• WO 95/19968 discloses inter alia aminophenyliminoimidazole derivatives which are used as alpha 2 agonists in anesthesia, in the treatment of pain, high blood pressure, hyperglucemia or as a sleep aid.
• WO 96/32939 discloses phenylimino-imidazoles, including those in which the phenyl ring in the meta position to the imino function has a primary or tertiary amine, an amide or imide.
• These Compounds described are considered alpha-1 L agonists and can advantageously be used in this property for the treatment of urinary incontinence.
• Incontinence is an involuntary loss of urine, i.e. a bladder weakness.
• the various manifestations of urinary incontinence include urge incontinence, reflex incontinence, overflow incontinence and stress or stress incontinence.
• One of the most common forms of urinary incontinence is stress incontinence or stress incontinence. This affects women in particular after more or less difficult births. The reason for this is that pregnancy and childbirth can easily weaken the pelvic floor.
• Other causes of incontinence can include innervation disorders of the pelvic floor, an inborn urethra that is too short, or injuries to the sphincter.
• alpha-1 L agonists in the treatment of urinary incontinence is advantageous because they act selectively on the adrenoceptors of the bladder and thus exert a significant influence on the urethertonization without significantly influencing the cardiovascular system.
• alpha 2 agonists such as clonidine would have a positive effect on night incontinence (Urology, 43 (3) (1994) 324-327).
• clonidine in particular there is a contrary observation that this substance can even promote incontinence (Clin. Biol. Res. 78 (1981) 101-103).
• EP-A-0 416 841 also deals with the influence of alpha agonists on bladder function. It describes that alpha 1 adrenoceptor blocking substances could be used to treat bladder occlusion. The observations according to US Pat. No. 4,226,773 also point in this direction. According to this document, pyrrazolyl-imino-imidazole derivatives can be used to promote urination. Other alpha 1 adrenergic imidazoles such as thiophene pyrroles can also be used to treat urinary incontinence (EP-A-0 599 697).
• the amino group is a tertiary amine and, on the other hand, that the other positions of the phenyl ring are substituted in a certain way.
• m-amino-phenylimino-2-imidazolidine derivatives of the general formula I are used to produce medicaments for the treatment of urinary incontinence:
• R 6 Me, Et, Pr or iPr
• R 7 Me, Et or Pr
• R 3 , R4, R 5 are each independently H, Me, F, Cl, Br, CH 2 F, CF 2 H and / or CF 3
• R 1 is Me, F, Cl, Br or CF, then R 1 is also H or Me.
• CH 2 F or CF 2 H is less preferred as a substituent for R 1 .
• CF 2 H difluoromethyl
• Pr propyl
• iPr isopropyl
• H hydrogen
• F fluorine
• Cl chlorine
• Br Bromine
• N stands for nitrogen.
• R 2 NR 6 R 7 , with R 7 : Me or Et and R 3 , R 4 , R 5 : are each independently H, F, Cl, Br and / or CF 3
• Ri can also be H or Me if R 4 is : F, Cl, Br, CF 3 .
• R 6 Me or Et, preferably Me,
• R Me or Et, preferably Me, R 3 : H, F, Br or CF 3 , R 4 : Cl, Br or CF 3 , R 5 : H, Br or CF 3 ,
• R 7 Me, R 3 : H, F, preferably H, R Cl or Br, R 5 : H or Br
• the compounds represented by the formula I can be in tautomeric equilibrium with the m-amino-anilino-2-imidazoline derivatives of the formula II:
• the atoms of the imidazole ring are numbered 1, 2, 3, etc., number 1 being assigned to one nitrogen atom and number 3 assigned to the other nitrogen atom. Accordingly, the imino group is attached to the carbon atom to which the number 2 is assigned.
• the atoms of the phenyl ring are numbered 1 ', 2', 3 ', etc., the carbon atom of the phenyl ring which is bonded to the imino group being referred to as 1' throughout.
• Another aspect of the present invention relates to the compounds of the above-mentioned general formulas I and / or II and their pharmacologically tolerable salts with the radicals R 1 to R 5 in all of the definitions mentioned, and to medicaments which contain these compounds.
• Hydrochloric acid hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, citric acid, lactic acid, acetic acid, propionic acid, malic acid, succinic acid, amino acid, in particular glutamic acid or aspartic acid, carbohydrate acids and acids derived from carbohydrates.
• Such salts can be important both for the pharmaceutical preparation, increase the stability, in particular long-term stability, of the compound and / or lead to an increase in bioavailability.
• Hydrochloride salts are preferred, depending on the compound, the monohydrochlorides or dihydrochlorides. The same applies to the preferred compounds.
• the compounds mentioned are distinguished from the compounds known from the prior art by their pharmacological properties, in particular with regard to bioavailability and / or their metabolism. It goes without saying that the most preferred compounds are those which are highly effective and bioavailable with little metabolic degradation. Another feature that is important for the selection of particularly suitable compounds for the treatment of urinary incontinence is the selectivity with which the corresponding compound acts on the bladder function without significantly influencing other body functions, particularly the cardiovascular system.
• the compounds mentioned and their pharmacologically acceptable acid addition salts can be prepared in suitable pharmaceutical formulations.
• suitable pharmaceutical formulations include all formulations that are suitable for medical use. This includes e.g. Solutions, suspensions, aerosols, powders, tablets, coated tablets, suppositories, creams etc.
• the compounds according to the invention can be used medically to treat diseases, especially for diseases of the bladder, especially for urinary incontinence.
• the use of the compounds according to the invention for the treatment of stress incontinence is most preferred.
• Another aspect of the present invention relates to processes for the preparation of the compounds mentioned, their pharmacologically acceptable acid addition salts and / or pharmaceutical preparations, and the use of the compound described for the preparation of further pharmacologically active derivatives thereof.
• test substances were administered orally to a group of 8 male fasting rats.
• animals from an identical second group were administered the test substances intravenously.
• 1 ml of blood samples were taken from the animals of both groups after defined times after administration (10 minutes, 30 minutes, 1 hour, 2 hours and 4 hours, the animals of the oral group additionally after 6 hours).
• the blood samples taken per group were mixed (8 ml).
• the content of the corresponding test substances in the blood was determined from the plasma for the respective time by HPLC (High Performance Liquid Chromatography) according to standard methods and related to the two groups.
• the enzyme CYP2D6 was allowed to act on the test substances. After 30 minutes, it was checked how much of the test substance used had been broken down by the enzyme.
• the decomposition rate is checked under the action of the HLM enzyme / 60 minutes.
• the compounds according to the invention can be prepared as described in WO 96/32939 on pages 11 to 16, which is hereby expressly incorporated by reference. Some of the compounds according to the invention can be prepared, for example, from the compounds described there, in particular the 2'-bromo-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine described on page 16.
• Step 1
• Example 3 3.6 g of a mixture of 4-bromo-2-methyl-3-nitroaniline and 4,5-dibromo-2-methyl-3-nitroaniline are reacted as in Example 3, step 4.
• the product is purified by chromatography (silica gel, mobile phase: cyclohexane / ethyl acetate (90/10).
• 1.9 g of N, N-dimethyl-4,5-dibromo-2-methyl-3-nitroaniline are obtained as a yellow powder.
• N, N-dimethyl-3-nitroaniline 25 g of N, N-dimethyl-3-nitroaniline are dissolved in 225 ml of DMF.
• 20 g of N-chlorosuccinimide dissolved in 190 ml of DMF are slowly added dropwise and the solution is stirred at RT. After 24 hours the solvent is evaporated. About 500 ml of ice are added to the red residue. The suspension is extracted three times with about 200 ml of diethyl ether each time. The ether phases are dried over Na 2 SO 4 , filtered and evaporated.
• Stages 1 and 2 are carried out as described for compound 6.
• KSCN 6.6 g KSCN are dissolved in 220 ml acetone at 10 ° C. 8 ml of benzoyl chloride are added. The solution is refluxed for 10 minutes and then cooled to 10 ° C. A solution of 17.5 g of 2-bromo-6-chloro-5-dimethylamino-aniline in 150 ml of acetone is slowly added dropwise. The mixture is boiled at reflux. After 3 hours, 500 ml of ice water are added and the aqueous phase is extracted three times with 100 ml of ethyl acetate each time. The organic phases are dried, filtered and evaporated. The residue is dissolved in 150 ml of ethanol and refluxed with 39 ml of aqueous KOH (50%). After 2 hours the solvent is distilled off.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Urology & Nephrology (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

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