IE910171A1 - New thiazole derivatives - Google Patents
New thiazole derivativesInfo
- Publication number
- IE910171A1 IE910171A1 IE017191A IE17191A IE910171A1 IE 910171 A1 IE910171 A1 IE 910171A1 IE 017191 A IE017191 A IE 017191A IE 17191 A IE17191 A IE 17191A IE 910171 A1 IE910171 A1 IE 910171A1
- Authority
- IE
- Ireland
- Prior art keywords
- ppm
- bromo
- preparation
- phthalimidoalkan
- formula
- Prior art date
Links
Classifications
-
- 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
Landscapes
- 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)
Abstract
New thiazole derivatives which are a substituted 4- or 5-( omega -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, a process for the preparation of said compounds by ring closure of a 3-bromo- omega -phthalimidoalkan-2-one with thiourea under mild conditions, followed by hydrazinolysis or hydrolysis with diluted hydrochloric acid of the resulting phthalimido derivatives and medicaments containing said derivates with formula (1) for the treatment of congestive heart diseases or for the treatment of allergic disorders.
Description
New thiazole derivatives.
io 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, Rx 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 present knowledge into three categories which are described, mainly for historical reasons, with the qualifications of H3-, H2and 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
-2IE 91171 —- 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 5 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-reoeptor offers wide perspectives for the treatment of congestive io 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 alkylami25 nothiazoles described in the aforementioned patent applications also differs from the process now claimed. Several authors have incidentally reported about examples of certain alkylamino-thiazoless G.J. Durant et al describe in J.Med.Chem. 18(9), p.905-909 (1975) 2-thiazolylethylamine and
-(2-aminoethyl)thiazole; s.Boyarski Labay describes in
Chem.Abstr. 66(11) ρ.4287ί 45307j 2- and 4-(/J-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)-4methy1th iaζ ο1e.
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 compara5 ble to that of histamine. Only M.Impicciatore et al. report in Agents and Actions, 20, p.3-4 (1987) about 2-amino-5-(2aminoethyl)-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 is inotropic effect.
A new series of substituted w-(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)thiazoles reported under formula 1, viz. the 2-amino-5-(2-aminoethyl)-4-methylthiazole (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 230 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 H2receptor 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 and H3-receptors.
-4The 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-w-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-«-phthalimidoalkan-2-ones (8) as indicated in reaction scheme (A) takes place by selective bromination with bromine in carbon tetrachloride of the corresponding w-phthalimidoalkan-2-ones (7) which may be obtai15 ned 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-e-phthalimidoalkan-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.
IE 91171
- 5 The invention is illustrated by the following examples:
All the chemicals and solvents used are commercially available unless stated otherwise.
Melting points were determined by a Mettler FP 5 device for the determination of melting points.
“H-NMR-spectra were determined with a Bruker WH-90 spectrophotometer and the chemical shifts £ (In ppm) with tetramethylsilane as reference.
Mass spectra are determined on a Varian Mat CHg 10 spectrometer or on a Mat 90 (Finnigan Mat, San Jose, U.S.A.).
Histamine H^-ac tivi ty was determined on the right-3ide atrium of the guinea pig as described by G.J. Sterk et al in Bur.J.Med. Chem.,19, p. 545-550 (1984).
- Histamine H^-binding was determined as described by 15 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 (1932) .
- Histamine ^-activities were determined on the guinea-pig 20 ileum as described by G.J, Menkveld and H. Timmerman in
Eur. J .Fharmacol. 186, 343-347 (1990).
IE 91171
- 6 Example I
6-brqmp-2-hexanone__( 6a )
6-3romo-2-hexanone (6-.a) 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 1,3dibromopropane, 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 0.0./M.S. Subsequently 170.0 g (1.00 mole) of the crude 2-methyl-3-carbethoxy-5,6-dihydropyrar.e together with 140 ml of concentrated aqueous HSrsolution (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
IE 91171 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.,
S3 , P 20l51d).
94-9SflC/12 mm Hg.
Mass spectrum M/Z (intensity in %). 180(0.14): 178(0.11);
137(6.3) ; 99 ( 100) .
2D ^H-NMR (CDClg): 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., tniplet (J = 6.3 Hz), 2H.
Sxamole II
—. * Μ — X. —· —l — — — — a. 4-phth_alimido-2-butanone__( 7.a_)
IS
The 4-phthalimido-2-butanone (7a) was prepared according to a modified process by H.Irai et al., Xogyo Kagaku Zasschi, S2, pages 32-85 (1959) cf. Chem.Abstr., 58, 5659 b (1963) and such as described in Dutch patent application
3800998, April 18,1988.
Melting point 108.5-li0°C LH-NMR (CDClg): 2.22 ppm, (J-7.0 Hz) , 2H; 3.96 ppm, (Reference: H.Irai et al. , 111-113 0 Cl.
singlet, 3H; 2.96 ppm., triplet triplet (J=7.0 Hs), 2H; 7,627.96 ppm., multiplet, 4H.
b . 5-ghthal imido-2-gentanone^ J 7_b )
The 5-phthalimido-2-pentanone (7a) is prepared according to Dutch patent application 8300998, April 18,1938.
Yield 53%
IE 91171 _ 8 .
Meiting point 72-74°0, ‘H-NMR (CDCl^); 1.39-2.12 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 (7,c)
The 6-phthalimido-2-hexanone (7b) is prepared as described for the 5-phthalimido-2-pentanone (7 a) in Dutch patent application 3800998, April 18,1988.
Yield 80%, viscous oil.
^HaNMR (CDC1O): 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+ 7.65-7.90 ppm., multiples, 4H. Example__III
3-Bromo-td-phchaiimido-2-alkanones (s'
General process:
To a solution of 0.5 mole of an appropriate oo-phthal imido-2-alkanone (7) in circa 500 mi of tetrachlorocarbon is cautiously added, with vigorous stirring, 30 g (0.5 mole) bromine at room temperature. After decoloration of the reaction mixture the stirring is continued at room temperat ure 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
IE 91171
- 9 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-( to-phthalimidoalky1)thiazoles (25).
Thus there were obtained:
a_>. -3~Br°roo-5-phthallmldo-g-gentanone (8.a) yield 95%, from 5-phthalimido-2-pentanone (7b).
*H-NMR (CDClj): 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), IH; 7.69 ppm., multiplet, 4H.
b ‘. .3T3.romo-6-phthal lmidq-2-hexanone__,(,3 b ) i yield 93%,from 6-phthalimido-2-hexanone (7c).
^H-NMR (CDClj): 1.74-2.22 ppm, multiplet, 4H ; 2.36 ppm., singlet, 3H; 3.46-3.90 ppm., multiplet, 2H; 4.36 ppm., triplet, (Js7,2 Hz), IH; 7.60-7.95 ppm., multiplet, 4H.
Example IV
- ( wj -phthal 1ml doalkylj -,4-mgth^l thlazol es ( 9.)
General process:
To a solution of 0.2 mole of a crude 3-bromo-OJ-phtha,'.imido-2-aIkanone (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 ia added with stirring, After
Έ91171
-10 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 concentrat ed, thereafter to the residue an ethylacetate/methanol mixture (1:1 v/v) is added. After stirring circa 30 minutes the precipfate obtained is filtered off, washed subsequently with ethylacetate and diethyl ether, thereafter the precipitate
i.s· vacuum dried.
Thus were obtained:
a .,^-Amino-S-j 2-phthalimidoethyl)^4-methy 1th1 azolehydrobpmide (9 a) yield 50%, from 3-bromo-5-phthalimido-2-pentanone <(8 a) and thioureum.
^H-NMR (Dg-DMSO): 1.98 ppm., singlet, 3H; 2.98 ppm., triplet (3=6.5 Hz), 2H; 3.78 ppm., triplet (J=6.5 Hz) 2H; 7.91 ppm., singlet, 4H; 9.05 ppm., broad singlex, 2H.
b . 2-amlno-5-(3-phthalimidopropy1)-4-methy1th i az ole dydrobromj.de__(9 b )
Yield 51%, from 3-bromo-6-phthalimido-2-hexanone (8b) and thioureum.
^H-NMR (Dg-DMSO): 1.61-2,04 ppm., multiplet, 2H, 2.15 ppm., singlet, 3H; 2.70 ppm., triplet (3=8.1 Hz), 2H; 3.64 ppm., triplet (J=6.6 Hz), 2H; 7.88 ppm., singlet, 4Ht 9.23 ppm., broad singlet, 2H.
c. 5-( 2-phthal1mi d oethy1)-4-methy1thiaζ ole hydrobroroi de__( 9 c) yield 40%, from 3-bromo-5-phthalimido-2~pentanone (8a) and thiof ormami de.
Melting point 207.4-210.66C .
^H-NMR (Dg-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., singlet, 4H; 9.23 ppm., broad singles, 2H.
IE 91171 _ 11 _
Sxample^V
4- or 5-(u)-aminoalky 1.),thiazoles_ 10 )
General process:
A solution of 0.1 mole of an appropriate OJ-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 i0 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, whioh 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 'oy using toluene. To the residue obtained acetone is subsequently added , ' thereafter the crystalline material is filtered off) rinsedwith acetone and diethyl ether, thereafter it is vacuum dried, If necessary there is recrystallized from an appropriate solvent.
Thus were obtained:
IE 91171
- 12 a.__^ami ηo-5-£2-amino ethyl ) - 4-me thylthiazole dihydro chloride (10a)
Yield 82%, from 2-amino-5-(2-phthalimidoethy1)-4-methy1thiazole hydrobromide ( 9 a).
1H-NMR (Dg-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 Cg^ NjS: 157.067) 'a.· _ 2-am inc-5-( 3-aminopropy_jJ -4-methyl thiazole dihydrochlorldem ( 10b2 Yield 90%, from 2-amino~5~(.3-phthaiimidopropyl)-4-methylthiazole hydrobromide ( 9 b).
H-NMR (Dg-DMSO): 1.66-2.02 ppm., multiplet, 2H; 2.16 ppm,, 15 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 (intensify in %): 171(28.9); 154(75.1); 127(100); 115(3.7).
M* =171.080 (calculated for 0?Κ NjS: 171.083).
-13Histamine W2-activity and binding of some
- (tu- aminoalkyL) thiazoles ( IE 91171
Table I nr.
10a b
histamine compound
NHz
, pD, SS.E {g*p. right atrium)
6,30 ±0,04
,2 ±0,1
,10 ±0,06
PKj±s.E (g.p. cortex)
.30 ±0,08 £,16 ±0,08
IE 91171
Claims (10)
1. ω-Aminoalkylthiazole, characterized in that a substituted 5 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, represents a straight or branched alkyl group containing 1-4 carbon atoms and R 2 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-o-phthalimidoalkan-2-one (8) with thiou15 rea 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 ω20 aminoalkylthiazole derivative, characterised in that one prepares a histamine H 2 -receptor active compound.
4. 2-amino-5-(2-aminoethyl)-4-methylthiazole. 25 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. -291171 —--efi Use of a compound or medicament according to one of the previous claims for the treatment of congestive heart disea5 ses whether or not accompanied by heart failure or for the treatment of allergic disorders.
5. 7. A process for the preparation of 3-bromo-w-phthalimidoalkan-2-ones characterized by selective bromination with 10 bromine of the corresponding w-phthalimidoalkan-2-ones.
6. 8. A process for the preparation of 5-(ω-phthalimidoalkyl)-4alkylthiazoles characterized by ring closure of a 3-bromo»wphthalimidoalkan-2-one with thiourea in dimethylformamide IS under mild conditions.
7. 9. 3-Bromo-u-phthalimidoalkan-2-ones.
8. 10. 5-(w-phthalimidoalkyl)4-alkylthiazoles. 20
9. 11. A process for the preparation of a compound of claim 1 substantially as hereinbefore described by way of Example.
10. 12. The product of a process as claimed in any of claims 2, 3, 7, 8 or 11.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL9000132A NL9000132A (en) | 1990-01-19 | 1990-01-19 | NEW THIAZOLE DERIVATIVES. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE910171A1 true IE910171A1 (en) | 1991-07-31 |
Family
ID=19856444
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE017291A IE910172A1 (en) | 1990-01-19 | 1991-01-18 | New thiazole derivatives |
| IE017191A IE910171A1 (en) | 1990-01-19 | 1991-01-18 | New thiazole derivatives |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE017291A IE910172A1 (en) | 1990-01-19 | 1991-01-18 | New thiazole derivatives |
Country Status (9)
| Country | Link |
|---|---|
| EP (2) | EP0511271A1 (en) |
| JP (2) | JPH05503694A (en) |
| AU (2) | AU7064491A (en) |
| CA (2) | CA2074180A1 (en) |
| IE (2) | IE910172A1 (en) |
| IL (2) | IL96997A0 (en) |
| NL (1) | NL9000132A (en) |
| WO (2) | WO1991010657A1 (en) |
| ZA (2) | ZA91419B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1918131B (en) * | 2004-02-05 | 2011-05-04 | 前体生物药物股份公司 | Novel inhibitors of glutaminyl cyclase |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2636037A (en) * | 1947-10-10 | 1953-04-21 | Sharp & Dohme Inc | 2-amino-4-piperidinoethyl-thiazole |
| FR2073427A1 (en) * | 1969-11-28 | 1971-10-01 | Sogeras | 4-methyl-5-ethyl-n-heterocyclic thiazoles - with antianoxic activity |
| FR2361111A1 (en) * | 1976-08-11 | 1978-03-10 | Roussel Uclaf | NEW DERIVATIVES OF 5-THIAZOLE ALKYLAMINE, A PROCESS FOR THEIR PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
| US4166860A (en) * | 1977-10-11 | 1979-09-04 | William H. Rorer, Inc. | Imidazole amidinoureas for stimulating H2 -receptors |
| US4474794A (en) * | 1982-03-19 | 1984-10-02 | Eli Lilly And Company | N-Thiazolylmethylthioalkyl-N1 -alkenyl (or alkynyl)guanidines and related compounds |
| NL8601585A (en) * | 1986-06-19 | 1988-01-18 | Vereniging Voor Christelijk Wetenschappelijk Onderwijs | N- (2-SUBSTITUTED ALKYL) -N-IMIDAZOL-4-YL ALKYL GUANIDINE. |
| NL8800998A (en) * | 1988-04-18 | 1989-11-16 | Cedona Pharm Bv | PROCESS FOR PREPARING AN SUBSTITUTION OR SUBSTITUTED 4 (5) - (OMEGA-AMINOALKYL) IMIDAZOLE. |
-
1990
- 1990-01-19 NL NL9000132A patent/NL9000132A/en not_active Application Discontinuation
-
1991
- 1991-01-18 EP EP91902805A patent/EP0511271A1/en not_active Withdrawn
- 1991-01-18 AU AU70644/91A patent/AU7064491A/en not_active Abandoned
- 1991-01-18 AU AU70581/91A patent/AU7058191A/en not_active Abandoned
- 1991-01-18 IE IE017291A patent/IE910172A1/en unknown
- 1991-01-18 IE IE017191A patent/IE910171A1/en unknown
- 1991-01-18 WO PCT/NL1991/000008 patent/WO1991010657A1/en not_active Application Discontinuation
- 1991-01-18 EP EP91902804A patent/EP0511270A1/en not_active Withdrawn
- 1991-01-18 CA CA002074180A patent/CA2074180A1/en not_active Abandoned
- 1991-01-18 JP JP3502573A patent/JPH05503694A/en active Pending
- 1991-01-18 WO PCT/NL1991/000007 patent/WO1991010656A1/en not_active Application Discontinuation
- 1991-01-18 JP JP3502574A patent/JPH05503096A/en active Pending
- 1991-01-18 CA CA002074175A patent/CA2074175A1/en not_active Abandoned
- 1991-01-21 ZA ZA91419A patent/ZA91419B/en unknown
- 1991-01-21 ZA ZA91418A patent/ZA91418B/en unknown
- 1991-01-22 IL IL96997A patent/IL96997A0/en unknown
- 1991-01-22 IL IL96998A patent/IL96998A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0511270A1 (en) | 1992-11-04 |
| JPH05503096A (en) | 1993-05-27 |
| AU7058191A (en) | 1991-08-05 |
| ZA91419B (en) | 1991-10-30 |
| JPH05503694A (en) | 1993-06-17 |
| 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0003640B1 (en) | Antisecretory guanidine derivatives, processes for their manufacture and pharmaceutical compositions containing them | |
| CS202515B2 (en) | Method of producing novel 4-hydroxy-2h-1,2-benzothiazine-3-carboxamide-1,1-dioxides | |
| NO170883B (en) | PROCEDURE FOR PREPARING 2-AMINO-5-HYDROXY-4-METHYLPYRIMIDINE DERIVATIVES | |
| HU176807B (en) | Process for preparing guanidino-thiazole and imidazole derivatives | |
| CA1111038A (en) | Antisecretory compounds | |
| HU182461B (en) | Process for producing new h-2 down-receptore antagonistic thiazole derivatives | |
| EP0010893B1 (en) | Antisecretory branched-chain heterocyclic guanidine derivatives, processes for their manufacture, intermediates, and pharmaceutical compositions containing said derivatives | |
| US4431652A (en) | 4-Hydroxy-5-substituted-3(2H)-isothiazolone-1,1-dioxide derivatives useful in treating urinary tract calcium oxalate lithiasis | |
| CA1256109A (en) | Process for the preparation of derivatives of 4, 5-dihydrooxazoles | |
| US4980356A (en) | 2-imino-6-polyfluoroalkoxybenzothiazole derivatives, and pharamaceutical compositions containing them and their treatment of medical conditions associated with the effects of glutamate | |
| CA1103245A (en) | Process for the manufacture of novel oxadiazolopyrimidine derivatives | |
| IE910171A1 (en) | New thiazole derivatives | |
| US4940790A (en) | 5-(3-alkyl-5-tert.butyl-4-hydroxyphenyl)-2-amino-6H-1,3,4-thiadiazines | |
| EP0592664A1 (en) | Novel diphenylthyazole derivative | |
| CA1074323A (en) | Thiopyrano (4,3-c) pyrazoles | |
| KR960012367B1 (en) | 2-alkylsulfinyl-4(3h)-quinazolinone derivatives | |
| EP0345533A1 (en) | Substituted 2-aminothiazoles as dopaminergic agents | |
| EP0055917B1 (en) | New benzothiazine derivatives, processes for preparation thereof and use thereof | |
| Previtera et al. | 3, 3′-Di (1, 3-thiazolidine-4-one) system. V. Synthesis and pharmacological properties of 3, 3′(1, 2-ethanediyl) bis-(2-heteroaryl-1, 3-thiazolidine-4-one) derivatives | |
| US3347857A (en) | Organic compounds | |
| US3835132A (en) | Morpholino-piperazinyl pyrimidines | |
| HU193827B (en) | Process for preparing thieno- and furo/2,3-c/pyrrole derivatives | |
| JPH02193965A (en) | Novel 2-halogenated n-indolylethyl-sulfonamide, preparation thereof,and use thereof in drug | |
| JPH0450305B2 (en) | ||
| US4868308A (en) | Preparation of N-phenyl(pyridyl) sulfonyldiamides |