AU7058191A - Thiazole derivatives - Google Patents

Thiazole derivatives

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Publication number
AU7058191A
AU7058191A AU70581/91A AU7058191A AU7058191A AU 7058191 A AU7058191 A AU 7058191A AU 70581/91 A AU70581/91 A AU 70581/91A AU 7058191 A AU7058191 A AU 7058191A AU 7058191 A AU7058191 A AU 7058191A
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ppm
bromo
phthalimidoalkan
preparation
histamine
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AU70581/91A
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John Charles Eriks
Geert Jan Sterk
Hendrik Timmerman
Henderikus Van Der Goot
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Cedona Pharmaceuticals BV
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Cedona Pharmaceuticals BV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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

Description

Thiazole derivatives The invention relates to new thiazole derivatives which are: a substituted 4- or 5-(ω-aminoalkyl)thiazole with formula 1, wherein X represents a nitrogen atom and Y represents a sulphur atom or alternatively X represents a sulphur atom and Y represents a nitrogen atom, n is 1-6, R1 represents a straight or branched alkyl group containing 1-4 carbon atoms and R2 represents an amino group.
The invention also relates to the acid addition salts of the compounds with the formula 1.
Histamine receptors are classified according to the presentt knowledge into three categories which are described, mainly for historical reasons, with the qualifications of H1-, H2- and H3-receptor.
Each of these classes of receptors presumably has its own and biologically specific function, in as far as they are present and dependent on the locating of such a receptor type in the organism involved.
In circumstances where a failure of the normal physiological system has occurred a treatment with endogenous or exogenous compounds may be necessary which may stimulate (agonistic activity) or inhibit (antagonistic activity) the receptor system.
From the above follows the great importance of compounds capable to agonize or to antagonize in a selective way the different classes of histamine receptors.
It is important to be able to dispose of selective histamine receptor active compounds in order to discriminate between the different receptor types not only from a scientific
(pharmacological) point of view, but also in therapeutic respect notably the stimulation of the histamine H2-receptor offers wide perspectives for the treatment of congestive heart diseases, accompanied by heart failure, and certain allergic disorders so that there exists a large interest from within the pharmaceutical industry for the development and application of selective, histamine H2-receptor active, compounds.
Thus the invention also relates to a process for the preparation of a ω-aminoalkylthiazole derivative in which one prepares a histamine H2-receptor active compound. Certain alkylaminothiazoles are known from the literature. Examples are described in several patent applications, e.g. FR 76 24 496, US 26 36 037, GB 15 26 038 and GB 11 49 110. None of these patent applications reveal the now claimed compounds, whereas the method of preparation of the alkylaminothiazoles described in the aforementioned patent applications also differs from the process now claimed. Several authors have incidentally reported about examples of certain alkylamino-thiazoles: G.J. Durant et al describe in J.Med.Chem. 18(9), p.905-909 (1975) 2-thiazolylethylamine and 5-(2-aminoethyl) thiazole; S.Boyarski Labay describes in Chem.Abstr. 66(11) p.4287: 45307J 2- and 4-(β-aminoethyl) thiazole; J.Jonas et al describe in Chem.Abstr. 58(5) column 4534d (1963) several 2-amino-4-(ω-aminoalkyl)thiazoles and U.H. Lindberg et al describe in Chem.Abstr. 68(23) p.10141: 105069m several aminoalkyl thiazoles e.g. 5-(2-aminoethyl)-4- methylthiazole.
Although thus far a large number of (substituted) analogues of histamine, in which the imidazole term has been replaced by another heterocyclic ring system, has been described in the literature, for a review of which reference is made to C.R. Ganellin in Pharmacology of Histamine Receptors, p.21-31 (1982), publishers Wright.PSG, none of the mentioned analogues displays an activity at the H2-receptor which is comparable to that of histamine. Only M.Impicciatore et al. report in Agents and Actions, 20, p.3-4 (1987) about 2-amino-5-(2- aminoethyl)-thiazole, which according to these authors is able to stimulate through an indirect pathway the histamine H2-receptor (as determined on the fundus of the guinea pig). In II Farmaco Ed.Sci., 41 (6), p.483-498 (1986) T.Vitali et al. describe this same 2-amino-5-(2-aminoethyl) thiazole reporting that this compound exhibits an activity on the right atrium of the guinea pig of 0.3% relative to the activity of histamine whereas this activity is related to the inotropic effect.
A new series of substituted ω-(thiazol-4 or 5-yl)alkyl derivatives has now been discovered which display a very selective and high histamine H2-receptor activity on the right atrium of the guinea pig, namely the above mentioned compounds with formula 1 and their acid addition salts. All this is clearly illustrated by a characteristic representative of the 4- or 5-(ω-aminoalkyl)thiazoleε reported under formula 1, viz. the 2-amino-5-(2-aminoethyl)-4-methylti 4sole (3) which is essentially a substituted sulphur analogue of the endogenous histamine (4) or which alternatively may be considered as a closed ring analogue of dimaprit (2).
Whereas endogenous histamine (4) is able to stimulate all previously mentioned types of histamine receptors, the 2- amino-5-(2-aminoethyl)-4-methylthiazole (3) can be displaced competitatively by cimetidine, while the intrinsic activity (related to the chronotropic effect) is equal to that of histamine, thus rendering it to be a full agonist for the H2- receptor with an activity twice as high as that of histamine. The 2-amino-5-(3-aminopropyl)-4-methylthiazole (10b) is a full H2-receptor agonist with an activity 30 times as high as that of the corresponding 4(5)-3-aminopropyl)-imidazole.
The 2-amino-5-(2-aminoethyl)-4-methylthiazole (3) shows however contrary to histamine (4), in the testing systems used not a single activity towards the E1 and H3-receptors. The 4- or 5-(ω-aminoalkyl) thiazole derivatives mentioned in the introduction with formula 1 may be obtained using a process not previously described in the literature in high yields by ring closure of a 3-bromo-ω-phthalimidoalkan-2-one (8) with thiourea in dimethylformamide under mild conditions, followed by hydrazinolysis or hydrolysis with diluted hydrochloric acid of the resulting phthalimido derivatives (9) as depicted in reaction scheme A.
The preparation of the 3-bromo-ω-phthalimidoalkan-2-ones (8) as indicated in reaction scheme (A) takes place by selective bromination with bromine in carbon tetrachloride of the corresponding ω-phthalimidoalkan-2-ones (7) which may be obtained according to a process described in the Dutch patent application 8800998. The necessary ω-haloketones (6) which are to be used for the preparation of the 3-bromo-ω-phthali- midoalkan-2-ones (8) are either commercially available or may be obtained in good yield according to a process described in the literature such as for example the process described in the Dutch patent application 65 11581.
The invention also relates to a medicament or a scientific (pharmacological) adjuvant which contains as the active ingredient a compound according to one of the formula 1 or an acid addition salt thereof. One may use the compounds or the medicaments according to the invention for the treatment of congestive heart diseases whether or not accompanied by heart failure or for the treatment of allergic disorders.
The invention is illustrated by the following examples:
All the chemicals and solvents used are commercially avail able unless stated otherwise .
Melting points were determined by a Mettler FP 5 device for the determination of melting points.
1H-NMR-spectra were determined with a Bruker WH-90 spectrophotometer and the chemical shifts δ (in ppm) with tetramethylsilane as reference.
Mass spectra are determined on a Varian Mat CH5 spectrometer or on a Mat 90 (Finnigan Mat, San Jose, U.S.A.).
Histamine H2-activity was determined on the
right-side atrium of the guinea pig as described by
G. J. Sterk et al in Eur. J. Med. Chem., 19, p. 545-550 (1984).
- Histamine H2-binding was determined as described by
G. J. Sterk et al in Agents Actions 18, 231 (1986).
- Histamine H1-activities were determined on the guinea-pig ileum as described by Emmett et al in J. Med. Chem. 25,
1168-1174 (1982).
- Histamine H3-activities were determined on the guinea-pig ileum as described by G. J. Menkveld and H. Timmerman in
Eur. J. Pharmacol. 186, 343-347 (1990).
Example I
6-bromo-2-hexanone (6a)
6-Bromo-2-hexanone (6a) is prepared according to a modified process as described in Dutch patent application 6511581 dated March 7,1966, cf. Chem. Abstr. 65, P20151d.
A mixture of 552 g (4 mole) of particulated anhydrous potassium carbonate, 404 g (2 mole) of freshly distilled 1,3- dibromopropane, 260g (2 mole) of freshly distilled acetyl acetic ester and 700 ml of absolute ethanol is heated with vigorous stirring until circa 60°C. After the mild exothermal reaction beginning at circa 50°C, the reaction mixture is refluxed for circa 5 hours. After cooling the reaction mixture the inorganic salts are filtered off and the residue is rinsed with absolute ethanol. The combined filtrates are subsequently vacuum concentrated, thereafter to the residue circa 250 ml of demineralized water is added. Subsequently it is extracted with toluene. The collected toluene phases are combined, dried on anhydrous sodium sulfate, filtered and subsequently vacuum concentrated.
Yield 73% on the basis of G.C./M.S. Subsequently 170.0 g (1.00 mole) of the crude 2-methyl-3-carbethoxy-5,6-dihydropyrane together with 140 ml of concentrated aqueous HBr- solution (48%) is refluxed with vigorous stirring for
3 hours, and a violent evolution cf carbondioxide gas
takes place. After cooling the reaction mixture the formed 6-bromo-2-hexanone (22a) is extracted by means of chloroform, the collected chloroform phases are washed with demineralized water to neutral reaction, thereafter dried on anhydrous sodium sulfate, filtered and vacuum concentrated. Subsequently the residue is subjected to fractionated distillation.
Yield 104 g (0.58 mole) which corresponds with 79.4%.
Boiling point 102-106°C/18 mm Hg. Reference: (Chem. Abstr., 65, P 20151d).
94-98°C/12 mm Hg.
Mass spectrum M/Z (intensity in %). 180(0.14): 178(0.11);
137(6.3); 99 (100).
1H-NMR (CDCl3): 1.50-2.06 ppm., broad multiplet, 4H; 2.14 ppm., singlet, 3H; 2.48 ppm., triplet (J=6.3 Hz),
2H; 3.40 ppm., triplet (J=6.8 Hz), 2H.
Example II
a. 4-phthalimido-2-butanone ( 7a)
The 4-phthalimido-2-butanone (7a) was prepared according to a modified process by H. Irai et al., Kogyo Kagaku
Zasschi, 62, pages 82-85 (1959) cf. Chem.Abstr., 58, 5659 b (1963) and such as described in Dutch patent application
8800998, April 18,1988.
Melting point 108.5-110°C (Reference: H.Irai et al., 111-113°C). 1H-NMR (CDCl3): 2.22 ppm, singlet, 3H; 2.96 ppm., triplet (J=7.0 Hz), 2H; 3.96 ppm, triplet (J=7.0 Hz), 2H; 7.62- 7.96 ppm., multiplet, 4H.
b. 5-phthalimido-2-pentanone (7b)
The 5-phthalimido-2-pentanone (7a) is prepared according to Dutch patent application 8800998, April 18,1988.
Yield 53% Melting point 72-74°C.
1H-NMR (CDCl3): 1.89-2.12 ppm., multiplet, 2H; 2.15 ppm., singlet, 3H; 2.51 ppm., triplet (J=7.2 Hz), 2H;
3.72 ppm., triplet (J=6.6 Hz), 2H; 7.67-7.92 ppm., multiplet, 4H.
c. 6-phthalimido-2-hexanone (7c)
The 6-phthalimido-2-hexanone (7b) is prepared as described for the 5-phthalimido-2-pentanone (7a) in Dutch patent application 8800998, April 18,1988.
Yield 80%, viscous oil.
1H=NMR (CDCl3): 1.48-1.80 ppm., multiplet, 4H; 2.14 ppm., singlet, 3H; 2.52 ppm., triplet (J-6.8 Hz), 2H; 3.70 ppm., triplet (J=6.3 Hz), 2H+ 7.66-7.90 ppm., multiplet, 4H.
Example III
3-Bromo-ω-phthalimido-2-alkanones (8)
General process:
To a solution of 0.5 mole of an appropriate ω-phthalimido-2-alkanone (7) in circa 500 ml of tetrachlorocarbon is cautiously added, with vigorous stirring, 80 g (0.5 mole) bromine at room temperature. After decoloration of the reaction mixture the stirring is continued at room temperature for circa 2 hours. Subsequently there is added circa 100 ml chloroform and 500 ml of demineralized water, thereafter it is stirred for 30 minutes. The water phase is subsequently removed and the organic phase is washed with demineralized water until neutral reaction. The organic phase is subsequently dried on anhydrous sodium sulfate, filtered and vacuum concentrated. The residue (viscous oil) is
used without any purification for the preparation of the
2-amino-4-methy-5-(Co-phthalimidoalkyl)thiazoles (25).
Thus there were obtained:
a. 3-Bromo-5-phthalimido-2-pentanone (8a)
yield 95%, from 5-phthalimido-2-pentanone (7b).
1H-NMR (CDCl3): 2.10-2.59 ppm., multiplet, 2H; 2.40 ppm., singlet, 3H; 3.82 ppm., triplet (J=6.3 HZ), 2H; 4.34 ppm., triplet (J=7.5 Hz), 1H; 7.69 ppm., multiplet, 4H.
b. 3-Bromo-6-phthalimido-2-hexanone (8 b)
yield 93%, from 6-phthalimido-2-hexanone (7c).
1H-NMR (CDCl3): 1.74-2.22 ppm, multiplet, 4H ; 2.36 ppm., singlet, 3H; 3.46-3.90 ppm., multiplet, 2H; 4.36 ppm., triplet, (J=7.2 Hz), 1H; 7.60-7.95 ppm., multiplet, 4H.
Example IV
5-(ω-phthalimidoalkyl)-4-methylthiazoles (9)
General process:
To a solution of 0.2 mole of a crude 3-bromo-ω-phthalimido-2-alkanone (8 ) in circa 100 ml of anhydrous dimethylformamide a solution of 0.2 mole of thioureum, respectively thioformamide, respectively an alkylthioamide in circa 100 ml of dry dimethylformamide is added with stirring. After the exothermal reaction the temperature may rise to circa 100°C, there is heated at circa 100°C for circa 3 hours. After cooling the reaction mixture is high vacuum concentrated, thereafter to the residue an ethylacetate/methanol mixture (1:1 v/v) is added. After stirring circa 30 minutes the precipifete obtained is filtered off, washed subsequently with ethylacetate and diethyl ether, thereafter the precipitate is vacuum dried.
Thus were obtained:
a. 2-Amino-5-(2-phthalimidoethyl)-4-methylthiazole- hydrobomide (9 a)
yield 50%, from 3-bromo-5-phthalimido-2-pentanone (8a) and thioureum.
1H-NMR (D6-DMSO): 1.98 ppm., singlet, 3H; 2.98 ppm., triplet (J=6.5 Hz), 2H; 3.78 ppm., triplet (J=6.5 Hz) 2H; 7.91 ppm., singlet, 4H; 9.06 ppm., broad singlet, 2H.
b. 2-amino-5-(3-phthalimidopropyl)-4-methylthiazole
hydrobromide (9 b)
Yield 51%, from 3-bromo-6-phthalimido-2-hexanone (8b) and thioureum.
1H-NMR (D6-DMSO): 1.61-2.04 ppm., multiplet, 2H, 2.15 ppm., singlet, 3H; 2.70 ppm., triplet (J=8.1 Hz), 2H; 3.64 ppm., triplet (J=6.6 Hz), 2H; 7.88 ppm., singlet, 4H; 9.23 ppm., broad singlet, 2H.
c. 5-(2-phthalimidoethyl)-4-methylthiazole hydrobromide ( 9c) yield 40%, from 3-bromo-5-phthalimido-2-pentanone (8a) and thioformamide.
Melting point 207.4-210.6°C.
1H-NMR (D6-DMSO): 1.99 ppm., singlet, 3H; 2.96 ppm., triplet (J=6.3 Hz), 2H; 3.76 ppm., triplet (J-6.3 Hz), 2H; 7. 92 ppm . , singl et , 4H ; 9 . 23 ppm . , broad s inglet , 2H . Example V
4- or 5-(ω-aminoalkyl)thiazoles (10)
General process:
A solution of 0.1 mole of an appropriate ω-phthalimido- alkylthiazole hydrobromide ( 9) in circa 400 ml of anhydrous methanol is refluxed with 0.2 mole of an 80%-aqueous hydrazine-hydrate solution for 5 hours. After cooling in ice the crystallized phthalhydrazine is filtered off and the clear filtrate is vacuum concentrated. Subsequently 105 ml of a 1 molar aqueous sodium hydroxide solution is added to the residue, thereafter there is high-vacuum concentrated at room temperature. The residue obtained is stirred with warm absolute ethanol, which is high-vacuum concentrated after filtration. After taking up the residue in absolute ethanol there is acidified with a concentrated aqueous
37%- hydrochloric acid solution until circa pH = 2,
thereafter the mixture is high-vacuum concentrated at
room temperature and residual water are azeotropically
removed by using toluene. To the residue obtained
acetone is subsequently added, thereafter the crystalline material is filtered off, rinsedwith acetone and diethylether, thereafter it is vacuum dried, If necessary there is
recrystallized from an appropriate solvent.
Thus were obtained:
a. 2-amino-5-(2-aminoethyl)-4-methylthiazole dihydrochloride (10a)
Yield 82%, from 2-amino-5-(2-phthalimidoe'thyl)-4-methylthiazole hydrobromide ( 9a).
1H-NMR (D6-DMSO): 2.19 ppm., singlet, 3H; 2.82-3.07 ppm. broad singlet, 4H; 8.34 ppm., broad singlet, 3H; 9.32 ppm., broad singlet, 2H.
Mass spectrum M/Z (intensity in %) : 157(5.0); 141(3.8);
127(5.0); 114(8.3).
M+ = 157.065 (calculated for C6H11N3S: 157.067) b. 2-amino-5-(3-aminopropyl)-4-methylthiazole dihydrochloride ( 10b). Yield 90%, from 2-amino-5-(3-phthalimidopropyl)-4-methylthiazole hydrobromide ( 9 b).
1H-NMR (D6-DMSO): 1.66-2.02 ppm., multiplet, 2H; 2.16 ppm., singlet, 3H; 2.57-3.03 ppm, multiplet, 4H; 8.15 ppm, broad singlet, 3H; 9.32 ppm., broad singlet, 2H.
Mass spectrum M/Z (intensity in %): 171(28.9); 154(75.1); 127(100); 115(9.7).
M+ = 171.080 (calculated for C7H13N3S: 171.083).
( l)

Claims (10)

CLAIMS:
1. ω-Aminoalkylthiazole, characterized in that a substituted 4- or 5-(ω-aminoalkyl) thiazole with formula 1, wherein X represents a nitrogen atom and Y represents a sulphur atom, n is 1-6, R1 represents a straight or branched alkyl group containing 1-4 carbon atoms and R2 represents an
amino group.
2. Process for the preparation of an ω-aminoalkylthiazole, characterized in that one prepares a 5-(ω-aminoalkyl) thiazole derivative with formula 1 as described in claim 1 by ring closure of a 3-bromo-ω-phthalimidoalkan-2-one (8) with thiourea in dimethylformamide under mild conditions, followed by hydrazinolysis or hydrolysis with diluted hydrochloric acid of the resulting phthalimido derivatives (9).
3. Process for the preparation according to claim 1 of an ω- aminoalkylthiazole derivative, characterized in that one prepares a histamine H2-receptor active compound.
4. 2-amino-5-(2-aminoethyl)-4-methylthiazole.
5. Medicament, or scientific (pharmacological) adjuvant, characterized in that it contains as the active ingredient a compound according to the formula 1 or a compound obtained according to claim 3 and 4 or an acid addition salt thereof.
6. Use of a compound or medicament according to one of the previous claims for the treatment of congestive heart diseases whether or not accompanied by heart failure or for the treatment of allergic disorders.
7. A process for the preparation of 3-bromo-ω-phthalimidoalkan-2-ones characterized by selective bromination with bromine of the corresponding ω-phthalimidoalkan-2-ones.
8. A process for the preparation of 5-(ω-phthalimidoalkyl)-4- alkylthiazoles characterized by ring closure of a 3-bromo-ω- phthalimidoalkan-2-one with thiourea in dimethylformamide under mild conditions.
9. 3-Bromo-ω-phthalimidoalkan-2-ones.
10. 5-(ω-phthalimidoalkyl)4-alkylthiazoles.
AU70581/91A 1990-01-19 1991-01-18 Thiazole derivatives Abandoned AU7058191A (en)

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NL9000132A NL9000132A (en) 1990-01-19 1990-01-19 NEW THIAZOLE DERIVATIVES.
NL9000132 1990-01-19

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CA (2) CA2074180A1 (en)
IE (2) IE910172A1 (en)
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EP0511271A1 (en) 1992-11-04
NL9000132A (en) 1991-08-16
IE910172A1 (en) 1991-07-31
IL96998A0 (en) 1992-03-29
IL96997A0 (en) 1992-03-29
CA2074180A1 (en) 1991-07-20
CA2074175A1 (en) 1991-07-20
ZA91418B (en) 1991-10-30
WO1991010657A1 (en) 1991-07-25
AU7064491A (en) 1991-08-05
WO1991010656A1 (en) 1991-07-25
IE910171A1 (en) 1991-07-31

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