CA2158994A1 - Heterocycle-containing amidine derivatives, their preparation and use - Google Patents

Heterocycle-containing amidine derivatives, their preparation and use

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Publication number
CA2158994A1
CA2158994A1 CA002158994A CA2158994A CA2158994A1 CA 2158994 A1 CA2158994 A1 CA 2158994A1 CA 002158994 A CA002158994 A CA 002158994A CA 2158994 A CA2158994 A CA 2158994A CA 2158994 A1 CA2158994 A1 CA 2158994A1
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Prior art keywords
alkyl
denotes
hcl
formula
compounds
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CA002158994A
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French (fr)
Inventor
Ernst-Otto Renth
Kurt Schromm
Ralf Anderskewitz
Franz Birke
Armin Fugner
Hubert Heuer
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Boehringer Ingelheim International GmbH
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Individual
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Publication of CA2158994A1 publication Critical patent/CA2158994A1/en
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
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    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
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Abstract

Compounds of the formula

Description

21~8994 ~
FILE, PIN IN THI~S A~ DE~
Case l/961-H/5 - 1 - T~9n~TRANSLATl~N

S014609J.56 Amidine derivatives containing heterocYclic qroups, the preparation and use thereof The invention relates to new amidine derivatives containing heterocyclic groups, the preparation thereof using conventional methods and their use as active substances in pharmaceutical compositions.

The new amidine derivatives correspond to the formula I . NH
Het - A ~

B /

wherein A denotes one of the groups X1-A1-X2 (II) X2-A1-X1 (III) -N N- (IV) wherein A1 denotes a straight-chained or branched bivalent aliphatic C26-group which may also contain a double or triple bond, or one of the groups ~",",~ CH2 Rll R12 (V) (VI) (VII) \~ < ~-.
(VIII) (IX) X1 denotes 0, S, SO, SO2, CH2, NH or -N N-X2 denotes 0, S, CH2 or -O

B denotes CH=CH, CH=N, S or ~_ \>

Het denotes a heterocyclic group or a heterocyclic system consisting of two or three condensed rings which may contain one to three substituents.

Chiral compounds of formula I may occur in the form of racemates, in enantiomerically pure or concentrated form and in the form of a base or as salts with inorganic or organic, particularly physiologically acceptable acids.

The following groups, in particular, are examples of heterocyclic groups or condensed systems in the sense of the definition given above:

21~8994 Rl Rl R,;:~X~\ ~, o~ \" , `\ >

ta) (b) Rl N-- ~ Rl N N

R2 ~--~ o/~ R2 `~ S

(c) (d) R13 __ ~ R13 ~/ ~
R ~- \/ ( e ) R14 0 ( f ) N~

l ~ ~ N - N

;~\Rl N N

R3 \~J\ R2 , ><
(g) R13 (h) 2158g9~

Rl ~ )I ~ +~J '1~ 2 R2 R5 1 ( j ) (i) (X3 = O, S, CH2, SO, so2, NRlO~
CH2 - CH2, CH=CH) Rl I

>=o R13 L "~ o (k) (1) Rl : I R

(m) (n) Rl I R
N~ O ~ ~

(o) (p) - 215899~ ~

R1 R1 / ~ N

// `~' \~/ >~ R2 ~ S///N

R3 ¦ R3 N N (q) ( r) N N
R13 ¦¦
\ . N

N/
~ _ N>< Rl R5 (s) \~, (t) \N N N ~
k~ ~---- N N

(u ) I-- N
(v) Rl Rl ,. ~
~i~ O / ~ ~\\0/' (w) (x) 21~8994 Rl Rl O

'~1 s ~ o (y) (z) 1 4 j ;~ 1 4 <r, S I S
(aa) 5 (cc) (bb) (dd) S
(ee) (ff ) 3 < ~ 1 4 \

N . ¦ R

(99) (hh) ( i i ) R--N --N N --N
5~ ~ N R--N ~N ~
N ~ O

( I i) (kk) 21~9~

(nn) (mm) () R ~ 3 ~ N 3 1 3 ._ (pp) (qq) In these formulae:

R~ and R2, which may be identical or different, denote CF3, halogen, R5, ORs, COR6, SR6, SOR6, SO2R6, SO2NRsR7, C(OH)RsR7 or together may also denote the bivalent groups -CR8=CR9-CH=CH-, -CH=CR8-CR9=CH-, -CR8=CH-CR9=CH-, -O-CHR~ o--CH2--, --O-CH2-O-, CH2 CH2 ~, -(CH2)34-, -NH-Co-o-, -NH-Co-CH -o--CO-CH2-O- or -CO-CH2CH2-O- bonded with adjacent C-atoms of the benzene ring, whilst these grou~s may in turn be substituted by C14-alkyl, R3 denotes halogen, OH, CF3, Rs~ OR6, COR6, CONRsR7, 2 ~ CH2 0 (C1 4 alkyl), SR6, SOR6, S02R6, SO2NR5R7 NH-CO-(C14-alkyl), NH-SO2-(C14-alkyl), NRsR7 or C(OH)RsR7, a heterocyclic 5-membered ring having l to 3 heteroatoms and of the formula D = E ,D _ E / D _ E
-N ¦ or Rlo-N t or L
.- G ~ G ~ G

215~994 (wherein D, E and G, which may be identical or different, denote CH, N, C-(C~4-alkyl) or C-phenyl and L denotes O or S), R4 denotes H, halogen, NH2, NH-(C14-alkyl), C14-alkyl, N(C14-alkyl)2, OH, C14-alkoxy, phenyl, Rs denotes H, C112-alkyl, pyridyl, phenyl, phenyl optionally substituted by halogen, C14-alkyl, C14-alkoxy or C25-acyl, or phenyl-(C14-alkyl), R6 denotes C11z-alkyl, phenyl, or phenyl optionally substituted by halogen, C14-alkyl, C14-alkoxy or C -acyl R7 denotes H or C112-alkyl, R8, R9 (which may be identical or different) denote H, OH, C14-alkyl, C14-alkoxy or C25-acyl, R10 denotes H or C14-alkyl, R11, R12, which may be identical or different, denote H, OH, halogen, CF3, C14-alkyl or C14-alkoxy, R13, R14, which may be identical or different, denote H, C14-alkyl, C14-alkoxy, phenyl, naphthyl, whilst these ring systems may be mono- or polysubstituted by identical or different groups selected from fluorine, chlorine, bromine, C14-alkyl, C14-alkoxy or pseudohalogens such as CN or CF3, or R13 and R14 denote pyridyl.

If A1 contains a double or triple bond, this is generally not adjacent to a heteroatom. Accordingly, A1 in this case preferably represents groups such as CH2-CH=CH-CH2 (cis or trans) or CH2-C-C-CH2.

g If A1 denotes -N\ /N-- X1 does not have this meaning. If A is linked to a nitrogen atom of the group Het (as for example in groups j to o), A is linked to this nitrogen atom via a carbon atom. In the present text the group A is in every case written in the way in which it is to be inserted in formula I. If R1, R2 and R3 occur side by side, R3 generally represents hydrogen only when at least one of the groups R1 and R2 is not hydrogen.

Preferred compounds within the scope of the above definitions are embraced by formula Ia:

NH
Het'-Xl -Al -X2 " ~ (Ia) wherein A1', X1', X2' and Het' have the following meanings:
A1' denotes (CH2)26, CH2~C6H4~CH2~
Z or E CH2-CH=CH-CH2, CH2-C--C-CH2;
X1' denotes 0, S;
X2' denotes 0, S;
Het' denotes a group of the above formulae a, b, e, f, g, k, n, wherein R1, R2 and R3, which may be identical or different, represent H, Rs~ OR5 or COR5 and R
and R2 together may also denote a fused ring.

The compounds of formula I are obtained by~methods known p~ se, particularly as follows:

215~9g4 l. Reaction of a compound of formula ¦ ~ NH (V) Het - A - C
OR (or -SR
B /

(wherein Het, R4, A and B are as hereinbefore defined and R preferably denotes a C14-alkyl group or benzyl) with ammonia in an alcohol such as methanol, ethanol, n-propanol, i-propanol, or in an inert solvent, e.g. dichloromethane, tetrahydrofuran, dioxane, at temperatures between about 0 and 50C, preferably at about 20C.

2. Reduction of an amidoxime of formula NOH
~ (VI) Het - A ~ C

B ~ NH2 (wherein Het, R4, A and B are as hereinbefore defined) by the action of hydrogen in the presence of a catalyst such as Raney nickel, palladium or platinum.
3. Compounds of formula I wherein X1 or X2 denotes o or S, can also be obtained according to-the following plan:

¦ NH
Het - Z + L-A-X2(l) ~ I

\ B /
(VII) (VIII) or ¦ NH
Het - Xl(2)-A-L + Z - ~ I

(IX) (X) (wherein A, B, Het, X1, X2 and R4 are as hereinbefore defined and L denotes a nucleophobic leaving group and Z denotes OH or SH).

The reaction is carried out in solvents such as dimethylsulphoxide, dimethylformamide, acetonitrile or alcohols such as methanol, ethanol or propauol with the addition of a base (metal carbonates, metal hydroxides, metal hydrides) at temperatures between about 0 and 140C or at the boiling temperature of the reaction mixture.

The phenols or thiophenols can also be used in the form of salts, e.g. the alkali metal salts.
Suitable nucleophobic leaving groups are halogens, for example Br, Cl or groups of sulphonic acids such as methanesulphonic acid or benzenesulphonic acid.

215 8 9~4 The starting materials V and VI are preferably prepared from the corresponding nitriles of formula ~' Het - A CN (XI) (wherein A, B, Het and R4 are as hereinbefore defined), and these may in turn be obtained analogously to the reaction according to process 3. The other method of synthesis consists in reacting the corresponding nitriles with HCl via the imide chloride stage or direct reaction with, for example, C16-alcohols or -benzylalcohol in the presence of an acid such as HCl.
Reaction of the nitriles with H2S in solvents such as pyridine or dimethylformamide in the presence of a base such as triethylamine and subsequent alkylation or benzylation results in compounds of formula V. Starting from carboxylic acid amides, which in other respects correspond to the compounds of formula V, the compounds of formula V are also obtained by reacting with a trialkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as dichloromethane, tetrahydrofuran or dioxane at temperatures between 0 and 50C, preferably at ambient temperature.

The corresponding amidoximes of formula VI may be obtained from the nitriles XI by reacting with hydroxylamine in alcohols, e.g. methanol, ethanol, propanol, isopropanol.

The starting materials of formulae VII, VIII, IX and X
can be prepared by conventional methods.

21~8~9~

The compounds according to the invention are therapeutically useful, particularly in the light of their LTB4-antagonistic activity. They are therefore suitable for use, particularly, in those diseases in which inflammatory and/or allergic processes are involved, e.g. IBD (inflammatory bowel diseases), allergic rhinitis; ARDS (adult respiratory distress syndrome), asthma, ulcerative colitis, psoriasis and also for treating gastropathy induced by non-steroidal antiphlogistics (NSAID). The new compounds may also be used in conjunction with other active substances, e.g.
antiallergics, secretolytics, ~2-adrenergics, steroids for inhalation, antihistamines and/or PAF-antagonists.
They may be administered by topical, oral, transdermal, nasal or parenteral route or by inhalation.

The therapeutic or prophylactic dose is dependent on the nature and gravity of the disease, as well as the potency of the individual compounds and the body weight of the patient.

The new compounds may be administered topically, orally, transdermally, parenterally or by inhalation. The compounds take the form of active ingredients in conventional preparations, e.g. in compositions consisting essentially of an inert pharmaceutical carrier and an effect dose of the active substance, such as plain or coated tablets, capsules, lozenges, powders, solutions, suspensions, aerosols for inhalation, ointments, emulsions, syrups, suppositories, etc. An effective dose of the compounds according to the invention is between 20 and 200 mg/dose, by oral route.
For inhalation, powders or solutions containing 0.5% to 5~ active substance should be used, each dose containing about 2 to 20 mg of active substance.

The new compounds can be combined, inter alia, with 215~94 antiallergics, secretolytics, ~2-adrenergics, steroids for inhalation or antihistamines.

The Examples which follow show some possible formulations of the preparations.

215899~

Formulation Examples 1. Tablets Composition:
Active substance according to the invention 20 parts by weight Stearic acid 6 parts by weight Dextrose 474 parts by weight The constituents are processed in the usual way to form tablets weighing 500 mg. If desired, the content of active substance may be increased or reduced and the quantity of dextrose reduced or increased accordingly.

2. Suppositories Composition:
Active substance according to the invention100 parts by weight Powdered lactose45 parts by weight Cocoa butter1555 parts by weight The ingredients are processed in the usual way to form suppositories weighing 1.7 g.

3. Powder for inhalation Micronised powdered active substance (compound of formula I; particle size about 0.5 to 7 ~m) is packed into hard gelatine capsules in a quantity of 5 mg, optionally with the addition of micronised lactose. The powder is inhaled using conventional inhalation devices, e.g. according to DE-A 3 345 722.

The compounds according to the invention were tested inter alia for their activity in the tests described 21~899~

below.

a) LTBC - Receptor bindinq test The binding of 3H-LTB4 (3nM) to vital U937 cells (differentiated human monocytary cell line with naturally expressed LTB4 receptors) is inhibited, in dosage dependent manner, by an increasing concentration of the test substance (incubation 2 hours at 0C). After the unbound 3H-LTB4 has been separated off by membrane filtration, the radioactivity of the bound LTB4 receptor/3H-LTB4 complex is quantified by scintillation measurement.
The affinity (inhibition constant Kj) was determined by repeated adaptation of a displacement curve to the measurements (program: "coupled mass equilibria" on Wang computer).

b) Aqqreqation of neutrophilic qranulocytes in the qulnea-plq Indicated by LTB4 in vitro (increase in light transmission in the aggregometer, recorded in mm;
each experiment repeated twice): inhibition 2 minutes after incubation with test substance in polydiol/DMSO.

c) Leukotrien-B~-indicated accumulation of neutrophiles in the mouse ear Evaluation of the neutrophilic influx by photometric measurement (mOD/min) of the myeloperoxidase activity (Bradley et al.: J.
Invest. Dermatol. 78, 206, 1982) in the skin of the ear. Increase 6 hours after topical treatment of the left ear with LTB4 (250 ng on each side) compared with the right ear (2 x 5 ~l acetone as 215899~

solvent).
Substance administered by oral route in 1~ tylose 300, 30 minutes before the LTB4 stimulation.

The Kj values from test a) for the compounds according to the invention are between 1 and 20 nmol/l, preferably below 10 nmol/l. Particular mention should be made of the favourable oral effect of the new compounds.

The Examples which follow illustrate the possible methods of preparing the compounds according to the invention. In the Tables, BS denotes base, whereas the acids contained in the salts are abbreviated as follows:
1. AC, 2. MS, 3. FU, 4. FU1.

The anions present in the corresponding salts are:

1 . CH3COO( - ), 2 . CH3SO3( - ), 3. HC-COO(-) 4. HC-C00(-Il 11 ( - )OOC-CH HOOC-CH

21~99~

Process 1:

Example 1 ~ ~ _ 0-(CH2)2-0 ~ H2 9.6 g of 4-[2-(2-benzothiazolyloxy)-ethoxy]-benzonitrile are dissolved in 100 ml of absolute dichloromethane and 100 ml of absolute ethanol. At about -15C, HCl gas is introduced for 4 hours. The mixture is left to stand overnight at ambient temperature, about 800 ml of ether are added and the solvent is decanted off from the crystals obtained. The residue is dissolved in 50 ml of ethanol and after the addition of 50 ml of ethanol saturated with ammonia the mixture is refluxed for 1.5 hours. The solvent is distilled off in vacuo and the residue is recrystallised from ethanol/diethylether.
2.5 g of 4-[2-(2-benzothiazolyloxy)-ethoxy]-benzamidine hydrochloride are obtained, m.p. 205-207C.

Process 2:

Example 2 CH3 ~ 1~ ~ S-(CH2)5 0 \~ / /< NH2 3.85 g of 4-[5-(5-methyl-2-benzoxazolyl-mercapto]-pentyloxy-benzamidoxime methanesulphonate are dissolved in 200 ml of methanol. After the addition of Raney nickel the mixture is hydrogenated at 50C under normal conditions until the calculated quantity of hydrogen has been taken up (about 5 hours). The catalyst is removed by suction filtering, the solvent is distilled off and the residue is recrystallised from isopropyl alcohol.
The methanesulphonate of the 4-[5-(5-methyl-2-benzoxazolyl-mercapto]-pentyloxy-benzamidine melts at 129-130~C.

21~899~1 Process 3:

Example 3 C6H5 1~ S-CH2-CH2-0 ~ ~ NH

HCl H20 1.6 g of 2-mercapto-5-phenyl-1,2,4-oxadiazole are dissolved in 40 ml of absolute dimethylformamide. After the addition of 270 mg of 80% sodium hydride dispersion the mixture is first stirred for half an hour at ambient temperature. It is then heated to 50C and a solution of 2 g of 4-bromoethoxy-benzamidine dissolved in 40 ml of absolute dimethylformamide is slowly added dropwise thereto. The mixture is allowed to react for a further 2 hours at 50C, then cooled and poured onto ice water.
The mixture is suction filtered, suspended in ethanol and ethereal hydrochloric acid is added until an acidic reaction is obtained. The compound which has dissolved in the meantime is precipitated in the form of the hydrochloride. This is suction filtered and recrystallised from water. After drying, 0.6 g of 2-[2-(4-amidino-phenoxy)-ethylmercapto]-5-phenyl-1,3,4-oxadiazole is obtained in the form of the hydrochloride (m-p-: 237 - 8C).

The following compounds can be prepared analogously to these Examples:

21~899~

Table I

Compounds of formula ~H
_ A

No. A ~alt wlth Mp. [C]
or base 1 -S-(CH2)3-0- HCl H20157-8 2 -S-(CH2)s-0- HCl 95-6 3 -S-(CH2)6-0- HCl.H20 98-9 4 -S-(CH2)4-0- HCl 143-4 -S-(CH2)2-0- HCl 218-9 21~899 1 Table II

Compounds of formula Ra ~H
Rb~ A _ // \\ //
S ~ NH2 No. A Ra Rb Salt with Mp.[C]
or base 1 -S-(CH2)3 0 C6H5 C6H5 HCl 219-20 -N N-(CH2)2-0- H H HCl 211 3 -O-(CH2)2-0- H H HCl 222 4 -S-(CH2)2-O- C6H5 H HCl.H20 102-3 -S-(CH2)3-O- C6H5 H HCl 108-9 6 -S-(CH2)4-O- C6H5 C6H5 HCl 187-8 7 -S-(CH2)s-0- H C6H5 HCl 164 8 -S-(CH2)3-O.- H C6H5 HCl 172 9 -S-(CH2)4-O- H C6H5 HCl lS3 S-(CH2)4-O- C6H5 H HCl.l~2O 110-1 21~89~4 , No. A Ra RbSalt with Mp. [C]
or - base 11 -S- (CH2) 2-- C6H5 C6H5HCl 258- 9 12 -S- (CH2)4-0 H H HCl 156-7 21 j'899~

Table III

Compounds of formula ~ \ O /~ NH2 No. A Ra Rb Salt with Mp. [C]
base S-(cH2)s-o CH3 H MS 12g-30 2 S-(CH2)2)O ~ ~ H H HCl 244-5 3 S-(CH2)s-O t-C4Hg H BS 65-70 H2o ~ H H 3 MS 207-9 O-(CH2)2-O H . H HCl ~18-20 6 S-(CH2)6-O H H HCl 140-1 7 S-(CH2)s-O H H HCl 184-5 8 S-(CH2)6-O H H BS 130-1 9 S-(CH2)s-O Cl H MS 160-2 S-(CH2)s-O H CH3 MS 160-1 21S8~94 No. A Ra Rb Salt with Mp. [C]
base 11 S- (CH2) 3- H H HCl 128-30 12 S- (CH2)4-O H H HCl 203 13 S- (CH2) 2- . H H HC1 187 14 S- (CH2) s- H H HCl - 104-5 O- (CH2) 3 -O H H HH2o 114 - 5 16 O- (CH2)4-O H H HCl 180-1 H2o 17 S- (CH2) 5- OCH3 H MS 142-4 18 S- (CH2) 4~ OCH3 H MS 163-4 19 S- (CH2)2-O CH3 H MS 177-8 S- (CH2) 5- F H MS ~145- 7 21 S- (CH2) 4- F H HCl 177-9 22 NH- (CH2) 4- H H FUl 238 21589~4 Table IV

Compounds of formula Ra / \

~o. A Ra RbSalt with Mp.[C]
or base 1 (CH2)5- C6~5 H HCl 161-2 2 S-(CH2)2-O H C6H5 HCl 190-1 3 S-(CH2)s-O H C6H5 HCl 160 4 S-(CH2)6-O H C6H5 HCl 166-7 S-(CH2)4-O C6H5 C6H5 HCl 170-l 6 S-(CH2)s-O C6H5 H HCl 109 7 S-(CH2)4-O C6H5 H HCl 142 8 S-(CH2)4-O H C6H5 HCl 146 21~8~

Table V

Compounds of formula Ra ~ < /~ ~2 No. A Ra Salt with Mp. [C]
bare 1 -S- (CH2) 4-O- H HCl 172-3 2 -S- (CH2) 3-- H HCl 156-7 3 -S- (CH2) 2-- H HCl 177-8 4 -S- (CH2) s-O- H HCl 110-2 -0- (CH2) 2-- H HCl 205-7 6 -S- (CH2) 6-- H HCl 148,5 50,5 7 -O- (CH2) - 1C(CH3)2 H MS 220-2 21~8~

No. A Ra Salt with Mp.[C]
base 8 S- (CH2) 5-0 C2H5 HCl 142-3 S - ( CH2 ) 2 - ~I H MS 16 5 21589~

Table VI

Compounds of formula Ra ~ 1l N A

Rc No. A Ra Rb RcSalt with Mp. [C]
or base 1 (CH2)4-0 H H H HCl 170 2 (CH2)4-0 H H CH3 HCl 81 3 CH2-CH=CH H H H HCl 145-55 4 CH2-C_C-CH2-0 H H H HCl 148-52 i-C3H70H

(CH2)4- Cl Cl H HCl 185-7 6 (CH2)4- l ~ ~ H H H HCl 180-90 ;

~/ ``. H H H HCl 259-64 /
_ _ 21~8994 Table VII

Compounds of formula Ra ~T

\~ ~ ~ A _ /~ \> ~

No. A Ra Rb XSalt with MP-[C]
or base 1 S-lCH2)3-O H H S HCl.H2O 170 2 S-(CH2)4-O H H S HCl 186-7 3 O-(CH2)2-O H H S HCl 209-10 NH
4 O-(CH2)4-O H C S 2HCl 274-5 O-(CH2)4-O OCH3 OCH3 S HCl 181-2 6 S-(CH2)2-O H H S HCl H2O 188-9 7 S-(CH2)2-O H H O HCl.H2O 237-8 8 S-(CH2)3-O H H O HCl 175 9 S-(CH2)4-O H H O HCl 182 21~899~

Table VIII

Compounds of formula ~T
NH
Ra No. A RaSalt with Mp. I c]
or base 1 -S-(CH2)2-0- CH3 2HCl 162-4 2 -S-(CH2)3-0- C6H5 HCl 207-8 3 -S-(CH2)4-0- C6H5 HCl 164 4 -S-(CH2)s-0- C6H5 BS 121-2 -S-(CH2)4-0- CH3 HCl 158-9 6 -S-(CH2)6-0- C~H5 FU1 22l-2 7 -S-(CH2)4-0- 4-(CH30)-c6H4 HCl 157-8 8 -S-(CH2)s-0- 4-(cH30)-c6H4 HCl 119-21 9 -S-(CH2)s-0- 3-(CH30)-c6H4 HCl 92-4 -S-(CH2)4-0- 3-(CH30)-c6H4 HCl 100-2 11 -S-(CH2)s-0- 2-(CH30)-C6H4 HCl 45-9 12 -S-(CH2)4-0 2-(CF3)-C6H4 FU 211 21~89~

No. A Ra Salt with MP-[C]
or base 13 -s-(cH2)4-o- 3-(cF3)-c6H4 FU 210 14 -S-(CH2)5-O- 3-(cF3)-c6H4 FU 202-3 -S-(CH2)4-O- 2-Naphthyl HCl 112-3 16 -S-CH2 ~ ~CH2O C6H5 FU1 229-30 17 -S-(CH2)5-O- 2-Naphthyl FUl 220-1 18 -S-(CH2)s-O- 2-(CF3)-C6H4 FUl 213 19 -S-(CH2)4-O- 1-Naphthyl FUl 226-7 -S-(CH2)5-O- 1-Naphthyl FUl 218-9 21 -SO-(CH2)5-O- C6H5 FU 232 22 -S-(CH2)2-O- C6H5 FU 239-40 23 -s-(cH2)3-o- 2-(CF3)-C6H4 FUl 222-3 24 -S-(CH2)6-O- 2-(CF3)-C6H4 FU1 226-7 -SO-(CH2)5-O- C6H5 FU1 215-6 26 -S-(cH2)5-o- 2-(CH3)-C6H4 FU1 227 27 -S-(CH2)5-O- 4-(CF3)-C6H4 FU1 228-9 28 -S-(CH2)5-O- 2-(C2H5)-C6H4 FU1 225 29 -S-(CH2)5-O- 2-(n C3H7)-C6H4 FU1 224 No. A Ra Salt with Mp.[C]
or base -S-(CH2)s-0- 2-(n-C3H7)-3-(CH30)~c6H3 FU1 223-4 31 -S-(CH2)5-0- 2-(CH30)-4-(CH30)-C6H3 FU1 211-2 32 -S-(CH2)5-0- 3-(CH30)-4-(CH30)-C6H3 FU1 213 33 -S-(CH2)5-0- 2-(CH30)-5-(CH30)-C~H3 FU1 ~219 34 -S-(CH2)s-0- 3-(CH30)-5-(cH30)-c6H3 FU1 215 -S-(CH2)s-0- 2-(n-C3H7)-3-OH~C6H3 HCl 154-7 36 S CH2- ~ -CH20 2-(cF3)-c6H5 FU1 228,5-9 37 -S-(CH2)s-0- 2-(CH30)-6-(CH30)-c6H3 FU1 212 38 -S-(CH2)s-0~ 2-(CH30)-3-(CH30)-C6H3 FU1 225 21~994 Table IX

Compounds of formula Het - A _ ~ , ~ NH
\ NH2 No. Het A Salt with Mp.[C
or base 1 ~ ~ N - (CH2)4-0 HCl 181 l~o `~
~/~ o ~

2 ~\ (CH2)4-0 HCl 219 ~,/ \ S

3 (CH2)4-0 HC1 213-4 N ~

(C~2)4-0 ~,5 213 4 (CH2)4-0 HCl 228-30 2158~9~

No . Het A Sa lt with Mp [ C]
base 6 ~ (Cll~)~ OIlCl la9-90 O N--~ ,//>

7 N O (CH2 ) 4 -O HCl 248 - 50 /' / \,~

o 8 ~ S- (CH2) 3~ HCl 143-5 `` N H 2 0 N N

S- (CH2) 2-2HCI , 233 -5 1~ ~. N
- ~ N ~N

10N--N~ S- (CH2) 2- HCl 145 _ N /

21~8~94 No.Het A Salt with Mp- [C]
or base 11 N (CH2) 2- HCl 235 /~ N~N
/\

12 ~ S- (CH2)2- 2H2Co 271 13 ` /N~ (CH2 ) 2 ~ HCl 174 - 4 CH 3 0 ~ Nl ~ H2 o CH30 ~ ~ N

14 , (CH2) 2- HCl 278-9 < H20 S N
~ r N N

~N~ S- (CH2) 2- HCl 293 N N
N

21S~994 No. Het A Salt with Mp. [C~
base 16 ~ S- (CH2) 2- BS 161-2 b~, ~ N--/

17 N~ (CH2) 2- HCl 25'7 N .H20 ~ N~

18 N S- (CH2) 2- HCl 253-4 . H20 N

215~994 No. Het ASalt with Mp. [C]
or base 19 C6Hs // ~ - (CH2) 5~ FU1 233-5 N~
N

~6 s // , ~ - (CH2) 4-O FUl 227-8 N\N
I

21 ~N S- (CH2) 4- HCl 263 N ~ N
l~N~ N

22 ~S~ S- (CH2) 4- HCl 148-9 1~ N~ N

23 l l - (CH2)4- FU1 226-7 C6 H5 N~N

215~

No. Het ASalt with-Mp.[oc]
or base 24 ,~ 0-(CH2)s-0 FUl 234 ~ ~ (Decomp) Cl N

Cl 0- (CH2)4 0 HCl 120 2 26 Cl - (CH2)5- FU1 237-8 ~ (Decomp) ~N~

27 Cl O-(CH2)4-0 HCl 178 N

28 ~ O-(CH2)s-0 FU1 223-4 (Decomp) ~ N~ Cl 29 Cl 0- (CH2)5-O FU1 219-20 ~ (Decomp) Il J
\N

215~4 No. He~ ASalt with Mp.[C]
or base O- (CH2) 4- FU122~ -30 ( Decomp ) ~N~Cl 31 Cl 0- (CH2) 4- HCl 157 ~,,;
N

32 ,~ S- (CH2) 5- HCl 148-9 N

33 / O- (CH2)s-O HC1 130-2 C6 H5~

34 ~. / O- (CH2) 2- HCl 188-9 ~ 6 H 5(~

35 N N S- (CH2) s- HCl 149 -50 N
\N

- 215~99~

No. Het A Salt with Mp.[C]
or base 36 N_N -(CH2)5- HCl 150-1 N// ~ ' \N

3 7 N _N S-(CH2)5-O HCl 174-5 ~HN~

38 c6 H5 O- (CH2)5-O FUl 236- 7 --N _N
\~
C 6 H \\ ~

39 C6 H5 S- (CH2)4-O HCl 150-1 --N N
\~
C 6 H ~\

6 5 S- (CH2)5- HCl 119-21 N ~

41 ~N S-(CH2)4 O HCl 154-5 215~994 No. Het ASalt with Mp. ["C]
or base 42 ~N S- (CH2)s-O MS 105-3 ~ ' o 43 S- (CH2) s-O AC 206-8 .., Table X

Compounds of formula N H
R c 3~

~N A N H
Ra Rb No. Ra Rb Rc A Salt Mp [C]
with or base 1 C6H5 H H -(CH2)4-0 HC1215-8 2 C6H5 H H -(CH2)5- BS129-30 3 C6H5 C6H5 H -(CH2)4- FU244-5 4 C6H5 C6H5 H -(CH2)s- FU249-50 H H C6H5 -(CH2)4-0 FU1226-7 6 2-(CH30)-C6Hs H H -(CH2)s-0 2HCl246-7 8 3-(CH30)-C6H5 H H -(CH2)5- FU1235 215899~

No Ra Rb Rc A Sa 1 tMp [ C ]

base 9 H H C6H5 - (CH2 ) 5 ~ FUl 220 -1 H H C6H5 -CH2- -CH2O FUl 223

Claims (9)

Claims
1. Amidine derivatives of the formula (I) wherein A denotes one of the groups X1-A1-X2 (II) X2-A1-X1 (III) (IV) wherein A1 denotes a straight-chained or branched bivalent aliphatic C2-6-group which may also contain a double or triple bond, or one of the groups (V) (VI) (VII) (VIII) (IX) X1 denotes O, S, SO, SO2, CH2, NII or - X2 denotes O, S, CH2 or -O B denotes CH=CH, CH=N, S or Het denotes a heterocyclic group or a heterocyclic system consisting of two or three condensed rings which may contain one to three substituents, R4 denotes H, F, Cl, Br, I, NH2, NH-(C1-4-alkyl), N(C1-4alkyl)2, OH, C1-4-alkoxy, C1-4-alkyl, phenyl, R11 and R12, which may be identical or different, denote H, OH, F, Cl, Br, I, CF3, C1-4-alkyl or -alkoxy, (whilst chiral compounds may be present in the form of racemates, in enantiomerically pure or concentrated form), each as a base or as salts with inorganic or organic acids.
2. Compounds according to claim 1, wherein Het denotes the groups (a) to (z):

(a) (b) (c) (d) (e) (f) (g) (h) (j) (i) (X3 = O, S, CH2, SO, SO2, NR10' CH2-CH2, CH=CH) (k) (l) (m) (n) (o) (p) (q) (r) (s) (t) (u) (v) (w) (x) (y) ((z) (aa) (cc) (bb) (dd) (ee) (ff) (gg) (hh) (ii) (jj) (kk) (ll) (nn) (mm) (oo) (pp) (qq) and R1 and R2, which may be identical or different, denote CF3, halogen, R5, OR5, COR6, SR6, SOR6, SO2R6, SO2NR5R7, C(OH)R5R7 or together may also denote the bivalent groups -CR8=CR9-CH=CH-, -CH=CR8-CR9=CH-, -CR8=CH-CR9=CH-, -O-CHR10-CH2-, -O-CH2-O-, -O-CH2-CH2-O-, -(CH2)3-4-, -NH-CO-O-, -NH-CO-CH2-O-, -CO-CH2-O- or -CO-CH2CH2-O- bonded with adjacent C-atoms of the benzene ring, whilst these groups may in turn be substituted by C1-4-alkyl, R3 denotes halogen, OH, CF3, R5, OR6, COR6, CONR5R7 CH2OH, CH2-O-(C1-4-alkyl), SR6, SOR6, SO2R6, SO2NR5R7, NH-CO-(C1-4-alkyl), NH-SO2-(C1-4-alkyl), NR5R7 or C(OH)R5R7, a heterocyclic 5-membered ring having 1 to 3 heteroatoms and of the formula or or (wherein D, E and G, which may be identical or different, denote CH, N, C-(C1-4-alkyl) or C-phenyl and L denotes O or S), R4 denotes H, halogen, C1-4-alkyl, NH2, NH-(C1-4-alkyl), N(C1-4-alkyl)2, OH, C1-4-alkoxy, or phenyl, R5 denotes H, C1-2-alkyl, pyridyl, phenyl, phenyl optionally substituted by halogen, C1-4-alkyl, C1-4-alkoxy or C2-5-acyl, or phenyl-(C1-4-alkyl), R6 denotes C1-12-alkyl, phenyl, or phenyl optionally substituted by halogen, C1-4-alkyl, C1-4-alkoxy or C2-5-acyl, R7 denotes H or C1-12-alkyl, R8, R9 (which may be identical or different) denote H, OH, C1-4-alkyl, C1-4-alkoxy or C2-5-acyl, R10 denotes H or C1-4-alkyl, R11, R12, which may be identical or different, denote H, OH, halogen, CF3, C1-4-alkyl or C1-4-alkoxy, R13, R14, which may be identical or different, denote H, C1-4-alkyl, C1-4-alkoxy, phenyl, naphthyl, whilst these ring systems may be mono- or polysubstituted by identical or different groups selected from fluorine, chlorine, bromine, C1-4-alkyl, C1-4-alkoxy or pseudohalogens such as CN or CF3, or R13 and R14 denote pyridyl.
3. Compounds according to claim 1 or 2 of the formula (Ia) .

wherein A1', X1', X2' and Het' have the following meanings:

A1' denotes (CH2)2-6, CH2-C6H4-CH2, Z or E CH2-CH=CH-CH2, CH2-CC-CH2;
X1' denotes O, S;
X2 ' denotes O, S;
Het' denotes a group of the above formulae a, b, e, f, g, k, n, wherein R1, R2 and R3, which may be identical or dlfferent, represent H, R5, OR5 or COR5 and R1 and R2 together may also denote a fused ring.
4. The compounds of formula wherein Rx represents and the acid addition salts thereof.
5. Pharmaceutical compositions, characterised in that they contain a compound according to claims 1 to 4.
6. Use of compounds according to claims 1 to 4 in the preparation of pharmaceutical compositions for the treatment of diseases in which inflammatory and/or allergic processes are involved, particularly asthma, ulcerative colitis, psoriasis and for treating gastropathy induced by non-steroidal antiphlogistic drugs.
7. Use of an effective dose of a compound according to claims 1 to 4 for treating diseases in which LTB4-antagonistic compounds can be used.
8. Use of an effective dose of a compound according to claims 1 to 4 for the treatment of diseases in which inflammatory and/or allergic processes are involved, particularly asthma, ulcerative colitis, psoriasis, and for treating gastropathy induced by non-steroidal antiphlogistics.
9. Process for preparing compounds according to claims 1 to 4 in a manner known per se, characterised in that a) a compound of formula (V) (wherein Het, R4, A and B are as defined and R preferably denotes a C1-4-alkyl group or benzyl) is reacted with ammonia in an inert solvent or b) an amidoxime of formula (VI) (wherein Het, R4, A and B are as defined) is reduced with hydrogen in the presence of a catalyst or c) compounds of formula VII are reacted with compounds of formula VIII or compounds of formula IX are reacted with compounds of formula X.
CA002158994A 1993-03-23 1994-03-18 Heterocycle-containing amidine derivatives, their preparation and use Abandoned CA2158994A1 (en)

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