SK117495A3 - Heterocycle containing amidine derivatives, their preparation and use - Google Patents

Abstract

Compounds having the formula (I), which is explained in detail in the description, may be prepared by conventional methods and used in standard galenic compositions for therapeutical purposes.

Description

Technical field

The invention relates to novel amidine derivatives containing heterocyclic groups, to their preparation using conventional methods and to their use as active ingredients in pharmaceutical compositions.

SUMMARY OF THE INVENTION

i ί.

!

The novel amidine derivatives correspond to the formula

X ¹ -A ¹ -X ² (II) x ² -and ¹ -x ¹ (III) / \ -N N- (IV)

where

A ^ · denotes a bivalent straight or branched chain C2-C8 aliphatic group which may also contain a double or triple bond, or one of

(IN)

(VI)

(VII)

(VIII)

(IX) χΐ denotes Ο, S, SO, SO2, CH2, NH or

\ __ /

X denotes O, S, CH 2, or denotes CH = CH, CH = N, S or

Het refers to a heterocyclic group or a heterocyclic system consisting of two or three fused rings, which may contain one to three substituents.

R ⁴ denotes H, F, Cl, Br, I, NH _2, NH- (C ₁ _ ₄ alkyl), N (C - ^ _ ₄ alkyl) 2, OH, C ^ _ ₄ -alkoxy, C ^ n-alkyl, phenyl, 19, 19

R ^x and R ^x , which may be the same or different, denote

H, OH, F, Cl, Br, I, CF ^ C ^ _ ₄ -alkyl or -alkoxy,

The chiral compounds of the formula I can exist in the form of racemates, in enantiomerically pure or concentrated form and in the form of a base, or as inorganic or organic salts, in particular of physiologically acceptable acids.

Specifically, the following groups are examples of heterocyclic. groups or condensed systems as defined above:

R ² (m)

(about)

S0 _2, NR ^10, CH ₂ CH _2, CH = CH)

(N)

(U)

(in)

R ¹

(y) (z)

(Aa)

R ⁵ (cc)

(Dd)

(Ee)

N ---- W

M (hh)

H --- “H

H

N ---- N

R ³ (ii)

H

O (kk) (U) (ii)

(Nn)

(mm) (mm)

(Pp)

(Qq>

In these formulas:

on R, which may be the same or different, denote CF ₃ , halogen, R ⁵ , OR ⁵ , COR ⁶ , SR ⁶ , SOR ⁶ , SO ² R ⁶ , SO ² NR ⁵ R ⁷ , C (OH) RR or together may also denote bivalent -CR ⁸ = CR ⁹ -CH = CH-, -CH = CR ⁸ -CR ⁹ = CH-,

-CR ⁸ = CH-CR ⁹ = CH-, -O-CHR ¹⁰ -CH ₂ -, -o-ch ₂ -o-,

_{-O-CH2 -CH2} -O-, - (CH _{2) 3} _ ₄ -, -NH-CO-O-, -NH-CO-CH ₂ -O-,

-CO-CH ₂ -OC-atoms or -CO-CH ₂ CH ₂ -O- attached to the side ring of the benzene ring, while these groups in turn may be substituted by _4- alkyl,

R ³ denotes halogen, OH, CF ₃ , R ⁵ , OR ⁶ , COR ⁶ , CONR ⁵ R ⁷ ,

CH ₂ 0H, CH ₂ -O- (C ₁ _ ₄ alkyl), SR ^6, SOR ^6, SO 2 R ^6, SO 2 NR ⁵ R ^7, NH-CO- (C ₁ _ ₄ alkyl, NH-SO ₂ - ( _L _ C ₄ -alkyl, NR ⁵ R ⁷ or 7

C (OH) R R, a heterocyclic 5-membered ring having 1 to 5 carbon atoms; 3 heteroatoms and formula

. ₌ G or R 10 ' ⁿ

or

G (wherein D, E and G, which may be identical or different, denote CH, N, C- (C ₁ _ ₄ alkyl) or C-phenyl and L denotes O or S), denotes H, halogen, ^ 2 ' NH (C ^ _ ₄ alkyl), C ^ _ ~ ₄ alkyl, N _(C14 alkyl) 2, OH, C _L _ ₄ -alkoxy, phenyl, R 5 denote H, e, ^L-C 12 ^- alkyl, , pyridyl, phenyl, phenyl optionally substituted by halogen, C ^ _ ₄ alkyl, C ^ _ ₄ -alkoxy or C 2-5 -acyl, or a phenyl (C - ^ _ ₄ alkyl),

Ro refers to the C ^ _- £ 2 l -yl ^_a »phenyl, or phenyl optionally substituted with halo, C £ _ ₄ -alkyl, C £ _ ₄ -alkoxy or C 2-5 -acyl, C denotes H or a - ^ _ ^ 2 ^-a lkyl, nq

R, R (which may be the same or different) denote H, OH, C £ _ ₄ alkyl, C - ^ _ ₄ -alkoxy, or C 2-5 acyl group ~, denotes H or C ₁ _ ₄ alkyl,

Ί 1 Ί 9

R, R, which may be the same or different, denote H, OH, halo, CF ^ C - ^ _ ₄ alkyl or C - ^ _ ₄ -alkoxy, R? 3, R? 4, which are the same or different, denote H, C ₄ alkyl, C £ _ ₄ -alkoxy, phenyl, naphthyl, whilst these ring systems may be mono- or polysubstituted by identical or different groups selected from fluoro, chloro, bromo, C _ £ ₄ -alkyl, C ₁₄ -alkoxy or pseudohalogens such as CN or CF 4, or R 13 and R 14 denote pyridyl.

If A · * · contains a double or triple bond, it is not generally bonded to a heteroatom. Therefore, A 1 in this case rather represents groups such as CH 2 -CH = CH-CH 2 (cis or trans) or CH 2 -C = C-CH 2.

If / \ _

IN /

X ¹ has no meaning. When A is bound to the nitrogen atom of the Het group (such as in groups j to o), A is bound to that nitrogen atom through a carbon atom. This application contains

A group in all cases written in the manner in which the formula is to be inserted in formula I. If R, R and R ^J occur side by side, R generally represents hydrogen only if at least 1 2 one of the groups R and R is not is hydrogen.

Preferred substances within the above definitions are included in formula Ia:

112 where A, X, X and Het 'have the following meanings:

A ¹ 'denotes (CH ₂ ) ₂ g, CH 2 -C 8 H ₄ -CH ₂ , Z or E' CH ₂ -CH = CH-CH _2> CH ₂ -C = C-CH ₂ ;

X ^ 'denotes 0, S;

X ^ 'denotes 0, S;

Het ´ denotes a group of the above formulas a, b, e, f, g, k, n, where a, which may be the same or different, represent H,, OR ^ or 5 12

COR and R and R together may also denote a fused ring.

Substances of formula I are obtained in particular by the following:

by known methods,

Reaction of a compound of formula

R ⁴

Het

First

(IN)

-SR (wherein Het,, A and B are as defined above and R preferably denotes a C 6-6 alkyl or benzyl group) with ammonia in an alcohol such as methanol, ethanol, n-propanol, i-propanol, or an inert solvent such as dichloromethane, tetrahydrofuran, dioxane at temperatures between about 0 and 50 ° C, preferably at about 20 ° C.

2. Reduction of the amidoxime of formula

(VI) (wherein Het, A, and B are as defined above) by treatment with hydrogen in the presence of a catalyst such as Raney nickel, palladium or platinum.

The compounds of formula I may be

Second

where X or X denotes 0 or S, obtained according to the following plan:

Het (VII) or

Het

(X) (ix) (wherein A, B, Het, X ¹ , X ² and R ⁴ are as defined above and L denotes a nucleophobic leaving group and Z denotes OH or SH).

The reaction is carried out in a solvent such as in dimethyl sulfoxide, dimethylformamide, acetonitrile or alcohols such as methanol, ethanol or propanol with the addition of a base (metal carbonates, metal hydroxides, metal hydrides) at temperatures between about 0 and 140 ^e C and at boiling the reaction mixture.

Phenols or thiophenols can also be used in the form of salts, for example alkali metal salts. Suitable leaving nucleophobic groups are halogens, for example Br, Cl or sulfonic acid groups such as methanesulfonic acid or benzenesulfonic acid.

The starting materials V and VI are preferably prepared from the corresponding nitriles of the formula

R ⁴

Het-A --- --- CN (where A, B, Het and R ⁴ are as defined above), and these can in turn be obtained analogously to the reaction of Method 3. Another method of synthesis involves reacting the corresponding nitriles with HCl via an imidochloride step or by direct reaction, for example with C 1-8 -alcohols or benzyl alcohol in the presence of an acid such as HCl. Reaction of nitriles with H 2 S in solvents such as pyridine or dimethylformamide in the presence of a base such as triethylamine and subsequent alkylation or benzylation yields compounds of formula V. Starting from carbocyclic acid amides which in other respects correspond to compounds of formula V, compounds of formula V are also obtained by reaction with a trialkoxonium salt, such as trimethyloxonium tetrafluoroborate in a solvent such as dichloromethane, tetrahydrofuran or dioxane, at temperatures between and 50 ° C, preferably at ambient temperature.

The corresponding amidoximes of the formula VI can be obtained from the nitriles XI by reaction with hydroxylamine in alcohols, for example methanol, ethanol, propanol, isopropanol.

Starting materials of formulas VII, VIII, IX and X may be prepared by conventional methods.

The compounds of the invention are therapeutically useful, particularly in light of their LTBβ antagonist activity. Therefore, they are particularly suitable for use in those diseases in which inflammatory and / or allergic processes are involved, for example IBD (inflammatory internal diseases), allergic rhinitis, ARDS (adult respiratory distress syndrome), asthma, ulcerative colitis, psoriasis and also for the treatment nonsteroidal anti-inflammatory drug-induced gastropathy (NSAID). These new agents can also be used in conjunction with other active agents, for example, antiallergic drugs, secretolytics, β 2 -adrenergics, steroids for inhalation, antihistamines and / or PAF antagonists. They may be administered topically, orally, transdermally, nasally or parenterally, or by inhalation.

The therapeutic or prophylactic dose depends on the origin and severity of the disease as well as the strength of the individual substances and the body weight of the patient.

These new agents can be administered topically, orally, transdermally, parenterally, or by inhalation. The substances take the form of the active ingredient in conventional preparations, for example in mixtures consisting essentially of an inert pharmaceutical carrier and an effective dose of the active ingredient, such as ordinary or coated tablets, capsules, lozenges, powders, solutions, suspensions and aerosols for inhalation, ointments, emulsions. , syrups, suppositories, etc. The effective dose of the compounds of the invention is between 20 and 200 mg / dose by the oral route. For inhalation, powders or solutions containing from 0.5% to 5% by weight of the active ingredient should be used, each dose containing about 2 to 20 mg of the active ingredient.

I

These new substances may be, inter alia, combined with antiallergic drugs, secretolytics, β 2 -adrenergics, steroids for inhalation or antihistamines.

I

DETAILED DESCRIPTION OF THE INVENTION j

The examples that follow show some possible formulations of the formulations.

Formulation examples

1. Tablets

Composition:,

Active Substance of the Invention 20 parts by weight stearic acid 6 parts by weight

Dextrose 474 parts by weight

The ingredients are processed in the usual manner to form 500 mg tablets. If desired, the active substance content may be increased or decreased and accordingly the amount of dextrose reduced or increased.

2. Suppositories

Ingredients:

Active ingredient of the present invention 100 parts by weight of lactose powder 45 parts by weight

Cocoa butter is 1555 parts by weight

The ingredients are worked up in the usual manner to form suppositories weighing 1.7 g.

3. Inhalation powder '

The micronized powder of the active substance (compound of formula I; particle size about 0.5 to 7 µηι) is packaged in hard gelatin capsules in an amount of 5 mg, optionally with the addition of micronized lactose. The powder is inhaled using conventional inhalation devices, for example according to DE-A 3 345 722.

The compounds of the invention were tested, inter alia, for

Their activity in the assays described below.

a) LTB ₄ -receptor binding assay

Binding of ³ H-LTB ₄ (3 nM) to U937 vital cells (a differentiated human monocyte cell line with naturally expressed LTB ₄ receptors) is inhibited, at a dose-dependent rate, by increasing the concentration of test substance (incubation for 2 hours at 0 ° C). After unbound H-LTB _{4 was} separated by membrane filtration, the radioactivity of the bound LTB ₄ Q receptor / H-LTB ₄ bound was quantified by scintillation counting. The affinity (K i inhibition constant) is determined by repeatedly adjusting the displacement curve to the measurements (program: coupled mass equilibria on a Vang computer).

(b) Aggregation of guinea pig neutrophil granulocytes

It was indicated by tb ₄ light intensity in aggregometer, the piece was repeated two times):

in vitro (permeability increase recorded in mm; each inhibition 2 minutes after incubation with test substance in polydiol / DMSO mixture.

c) Leukotrien-B ₄ -induced neutrophil accumulation in the mouse ear.

Evaluation of neutrophil influx by photometric measurement (mOD / min) of myeloperoxidase activity (Bradley et al. '.

J. Invest. Dermatol. 78. 206, 1982) on the scalp.

Increase 6 hours after topical application to the left ear with LTB ₄ (250 ng on each side) compared to the right ear (2 x 5 μΐ acetone as solvent).

The compound was administered by the oral route in 1% Tylose 300, 30 minutes before LTB ₄ stimulation.

Test a) values for the compounds of the invention are between 1 and 20 nmol / L, preferably below 10 nmol / L. Special mention should be made of the beneficial oral effect of the new substances.

'U'

The examples that follow illustrate possible methods for preparing the compounds of the invention. In the Tables BS indicates the base, while the acids contained in the salts are truncated as follows:

1. AC,

2. MS,

I

3. FU,

4. FU1.

The anions present in the corresponding salts are:

First ch ₃ coc / ^_ ) Second ch ₃ so ₃ () Third HC-COO ( ') 4th HC-COC / ^-) ^ / OOC-CH II HOOC-CH

Method 1: Example 1

9.6 g of 4- [2- (2-benzothiazolyloxy) -ethoxy] -benzonitrile were dissolved in 100 ml of absolute dichloromethane and 100 ml of absolute ethanol. HCl gas was introduced at about -15 ° C for 4 hours. The mixture was allowed to stand overnight at room temperature, about 800 mL of ether was added and the solvent was decanted away from the obtained crystals. The residue was dissolved in 50 ml of ethanol and, after addition of 50 ml of ethanol saturated with ammonia, the mixture was refluxed for 1.5 hours. The solvent was distilled off under vacuum and the residue was recrystallized from ethanol / diethyl ether. 2.5 g of 4- (2- (2-benzothiazolyloxy) -ethoxy] -benzamidine hydrochloride, m.p. 205-207 ° C, were obtained.

. CH3SO3H

3.85 g of 4- [5- (5-methyl-2-benzoxazolyl-mercapto) -pentyloxy] benzoamidoximethanesulfonate were dissolved in 200 ml of methanol. After addition of Raney nickel, the mixture was hydrogenated at 50 ° C under normal conditions until the calculated amount of hydrogen (about 5 hours) was captured. The catalyst was removed by suction on a filter, the solvent was distilled off under vacuum and the residue was recrystallized from isopropanol. 4- [5- (5-Methyl-2-benzoxazolyl-mercapto) -pentyloxy] -benzamidine methanesulfonate melts at 129-130 ° C.

Method 3:

Example 3

s-ch _2. -ch ₂

j. HCl H ₂ O 3; 1.6 g of 2-mercapto-5-phenyl-1,2,4-oxadiazole were dissolved in 40 ml of absolute dimethylformamide. After adding 270 mg. The 80% sodium hydride dispersion was first stirred at room temperature for one and a half hours. It then warms up. The solution was stirred at 50 ° C and a solution of 4-bromoethoxybenzamidine dissolved in 40 ml of absolute dimethylformamide was slowly added dropwise. The mixture was allowed to react for an additional 2 hours at 50 ° C, then cooled and poured onto ice water. The mixture was suction filtered, suspended in ethanol, and ethereal hydrochloric acid was added until an acidic reaction was achieved. The compound so far dissolved was precipitated as the hydrochloride. This was suction filtered and recrystallized from water. After drying, 0.6 g of 2- (2- (4-amidino-phenoxy) -ethyl mercapto] -5-phenyl-1,3,4-oxadiazole was obtained as the hydrochloride (mp: 237-238 ° C).

Claims (9)

PATENT CLAIMS Amidine derivatives of formula I Het-A NH NH ₂ where A denotes one of the groups X ¹ -A ¹ -X ² (II) X ² -A ¹ -X ¹ (III) / "\ -N N- \__FROM (IV) wherein denotes a bivalent straight or branched chain C 2-8 aliphatic group which may also be a bond or one of the double or triple groups CH ₂ (VI) (VIII) (IX) X ^ · denotes Ο, S, SO, SO,, CH 2, NH or 2 * · X denotes O, S, CH 2, or Het denotes a heterocyclic group or a heterocyclic system consisting of two or three fused rings which may contain one to three substituents, * R ² denotes H, F, Cl, Br, I, NH 2, NH (C ^ - ^ - alkyl), N (C ₁ _ ₄ alkyl) _2, OH, C ₁ _ ₄ -alkoxy, C ₁ _ _4- alkyl, phenyl, R and R, which may be the same or different, denote H, OH, F, Cl, Br, I, CF 3, C ₁ _ ₄ alkyl or -alkoxy, (chiral agent may be present in the form of racemates, in enantiomerically pure or concentrated form), all in base form or as salts with inorganic or organic acids. Substances according to claim 1, wherein Het denotes groups (a) to (z): (a) (b) (c) N - N (g) _r 13 (h) (i) (X ³ = O, S, CH ₂ , SO, S0 ₂ , NR ¹⁰ CH ₂ -CH ₂ , CH = CH 11 ' N ----- N (t) (v) (y) (z) (a3) (cc) (bb) (ee) n ---- w N (ff) N ---- N R ³ (hh) (ii) R ¹³ II O (U) (also J) (kk) (ρρ) <qq> and 1 7 R and R, which may be the same or different, denote CF ₃ , halogen, R ⁵ , OR ⁵ , COR ⁶ , SR ⁶ , SOR ⁶ , SO ² R ⁶ , SO ² NR ⁵ R ⁷ , C (OH) R ^J R 'or together may also be bivalent groups -CR ⁸ = CR ⁹ -CH = CH-, -CH = CR ⁸ -CR ⁹ = CH-, -CR ⁸ = CH-CR ⁹ = CH-, -o-chr ¹⁰ -ch ₂ -, -o-ch ₂ -o-, -o-ch ₂ -ch ₂ -o-, - (CH ₂ ) ₃ - ₄ -, -nh-co-o-, -nh-co-ch ₂ -o-, _-CO-CH2-O- or -CO-CH ₂ CH ₂ -O- attached to the side C-atoms of the benzene ring, while these groups may in turn be substituted by C ^ _ ₄ alkyl, R ³ denotes halogen, OH, CF ₃ , R ⁵ , OR ⁶ , COR ⁶ , CONR ⁵ R ⁷ , CH ₂ OH, CH ₂ -O- (C ₁ _ ₄ alkyl), SR ^6, SOR ^6, SO 2 R ^6, SO 2 NR ⁵ R ^7, NH-CO- (C ₁ _ ₄ alkyl, NH-SO ₂ - ( C ₁ _ ₄ alkyl, NR ⁵ R ^7, or 5 7 C (OH) RR, heterocyclic 5-membered ring containing 1 to 3 heteroatoms and of the formula or (wherein D, E and G, which may be identical or different, denote CH, N, C- (C ₁ _ ₄ alkyl), or C-phenyl and L denotes (O or S), $ R ⁴ denotes H, halo, C ₄ alkyl, NH _2, NH (C ^ _ ₄ alkyl), N (C ₁ _ ₄ -alkyl) 2 OH, C £ _ ₄ -alkoxy or phenyl, R 5 e denote H, ^C l-12 alkyl, pyridyl, phenyl, phenyl optionally substituted with halo, C ₄ alkyl, C £ _ ₄ alkoxy or C ₂ _5-acyl, or phenyl- (C £ _ ₄ alkyl) . R ⁶ denotes a C £ _ J-alkyl, phenyl, or phenyl optionally monosubstituted with halo sub *, C ^ _ ₄ -alkyl, C £ _ ₄ -alkoxy or C ₂ _5 acyl, t R denotes H or alkyl Ci_i _2, R s, R ^s (which may be the same or different) denote H, OH, C s - ^ _ ₄ alkyl, C £ _ ₄ -alkoxy or C ₂ _g acyl ,! l ^[1U R denotes H or a C ₄ alkyl, 1112 i R, R, which may be the same or different, denote H, t. OH, halogen, CF 4, C _1-4 -alkyl or C _1-4 -alkoxy which may be the same or different denote H, C _1-4 -alkyl, C _1-4 -alkoxy, phenyl, naphthyl, whereas these ring systems may be mono- or polysubstituted by the same or different groups selected from fluorine, chlorine, bromine, C _1-4 -alkyl, C _1-4 -alkoxy or pseudohalogens such as CN or CF 3, or R 13 and R ¹⁴ denote pyridyl. Substances according to claim 1 or 2, model 1a: (Ia), 1, 1 X, X, and Het 'have the following meanings: A ¹ ' denotes (1-H ₂ ) ₂ -6 'CH ₂ -C ₈ H ₄ -CH ₂ , Z or E ch ₂ -ch = ch-ch ₂ , ch ₂ -oc-ch ₂ ; X ¹ ' denotes 0, S; X ² ' denotes 0, S; Het ’Indicates a group of the above formulas a, b, e, f, g, k, n, wherein R ¹ , R ² and R ³ , which may be same or different, represent H, R ³ , OR ³ or COR ^J and R ^x and R ^z together may also denote condensation circle. 4. Compounds of formula ^c 6 ^h 5 __S S- (CH ₂ ) 5 -O-1N ^X II - (CH ₂ ) λ - O - R ^X where R ^x represents and their acid addition salts. In f <i Pharmaceutical compositions comprising a compound according to claims 1 to 4. Use of the substances according to claims 1 to 4 for the preparation of pharmaceutical compositions for the treatment of diseases in which inflammatory and / or allergic processes are involved, in particular asthma, wasting colitis, psoriasis and also for the treatment of gastropathy induced by non-steroidal anti-inflammatory drugs. Use of an effective dose of the substances according to claims 1 to 4 for the treatment of diseases in which LTB ₄ antagonists can be used. Use of an effective dose of the substances according to claims 1 to 4 for the treatment of diseases involving inflammatory and / or allergic processes, in particular asthma, ulcerative colitis, psoriasis, and also for the treatment of gastropathy induced by non-steroidal anti-inflammatory drugs. A process for the preparation of the substances according to claims 1 to 4 in a manner known per se, characterized in that: (a) a substance of the formula Het (or -SR (V) (wherein Het, R ⁴ , A and B are as defined above and R preferably denotes a C 1-4 alkyl or benzyl group) is reacted with ammonia in an inert solvent; or (b) an amidoxime of formula Het R ⁴ of NOH \ nh ₂ (VI) (where Het, R ⁴ , A and B are as defined above) is reduced by treatment with hydrogen in the presence of a catalyst or (c) substances of formula VII react with substances of formula VIII or substances of formula IX react with substances of formula X.