CA2074175A1 - Thiazole derivatives - Google Patents

Thiazole derivatives

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Publication number
CA2074175A1
CA2074175A1 CA002074175A CA2074175A CA2074175A1 CA 2074175 A1 CA2074175 A1 CA 2074175A1 CA 002074175 A CA002074175 A CA 002074175A CA 2074175 A CA2074175 A CA 2074175A CA 2074175 A1 CA2074175 A1 CA 2074175A1
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Canada
Prior art keywords
omega
ppm
bromo
phthalimidoalkan
formula
Prior art date
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Abandoned
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CA002074175A
Other languages
French (fr)
Inventor
John C. Eriks
Geert J. Sterk
Henderikus Van Der Goot
Hendrik Timmermann
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Cedona Pharmaceuticals BV
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Individual
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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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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Cardiology (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

~ 091/1~56 -1- 2 0 7 4 l`i ~ z ; ' ~ ~i , Thiazole derivatives l~ The invention relates to new thiazole derivatives which are:
a substituted 4- or 5-(~-aminoalkyl)thiazole with formula.l, wherein X represents a nitrogen atom and Y represents a sulp-hur atom or alternatively X represents a sulphur atom and Y
represents a nitrogen atom, n is 1-6, Rl represents a 15 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 l.
20 Histamine receptors are classified according to the present knowledge into three categories which are described, mainly for. historical reasons, with the qualifications of Hl-, H2-and H3-receptor..
.~-. Each..of these classes o receptors-.presumably has its own and 25 : biologically specific function, in as far as they are present and dependent on the locating of 8UCh a receptor.type in the - organism involved.
In circumstances where a failure of the normal physiological system has occurred.a treatmént with endogenous or exogenous compounds may be necessary which may stimulate (agonistic activity) or inhibit (antagonistic activity) the receptor syste~.
From the above follows the great importance of compounds ... .. .. . ~ ~ -, , . ,. , , . ~ ~ . :
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207~1:75i~
WO9l/1~56 ,i ~ ~ ~ PCT/NL91/~0 capable to agonize or to antagonize in a selective way the different classes of-hi~tamine receptors.
It is important to be able to dispose of selective histamine s 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 o 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.
lS
Thus the invention also relates to a process for the prepara-tion of a ~-aminoalkylthiazole derivative in which one prepa-res 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 alkylami-nothiazoles described in the aforementioned patent applicati-ons also differs from the process now claimed. Several authors have incidentally reported about examples of certain alkylamino-thiazoles: G.~. 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: 45307; 2- and 4-(~-aminoethyl)thi-azole; J.Jonas et al describe in Chem.Abstr. 58(5) column 4534d (1963) several 2-amino-4-(~-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 literatuxe, for a review of which reference is made to ~-j wos1/l~s6 -3- 2 ~ 7 5 PCT/NLg1/~07 ..... .

C.~. Ganellin in Pharmacoloqy of Histamine Receptors, p.21-31 (1982), publishers Wright.PSG, none of the mentioned analogu-es displays an activity at the H2-receptor which is compara-s ble 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 ~2-receptor (as determined on the fundus of the guinea pig).
In Il 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 ~-(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 thi8 iS clearly illustrated by a characteristic representa-tive of the 4- or 5-(~-aminoalkyl)thiazoles reported under formula 1, viz. the 2-amino-5-(2-aminoethyl)-4-methylthiazole (3)~ which is essentially a substituted sulphur analogue of 2s the endogenous histamine (4l 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-s-(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-~mino-5-(2-aminoethyl)-4-methylthiazole (3) shows however contrary to histamine (4), in the testing systems used not a single activity towards the Hl and H3-receptors.

.~ .

: , .
' ' ' ' 2~7417~
W091/l~56 '~ J 4 PCT/NL91/

The 4- or 5~ aminoalkyl)thiazole derivatives mentioned in the introduction with formula 1 may be obtained using a pro-ces~ not previously described in the literature in high 5 yields by ring closure of a 3-bro~o-~-phthalimidoalkan-2-one (8) with thiourea in dimethylformamide under mild conditions, followed by hydrazinolysis or hydrolysis with diluted hydro-chloric 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 cor-responding ~-phthalimidoalkan-2-ones (7) which may be obtai-15 ned according to a process described in the Dutch patentapplication 8800998. The necessary ~-haloketones (6) which are to be used for the preparation of the 3-bromo-~-phthali-midoalkan-2-ones (8) are either commercially availa~le or may be obtained in good yield according to a process described in 20 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 25 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.
. .
~ . . .

~ O91/l~56 2 ~ 7 4 1 7 a PcT/NLg1toono7 The invention is illustrated by the following examples:
All the chemicals and solvents used are commercial-ly available unless stated otherwise.
Melting points were determined by a Mettler FP 5 5 device for the determination of melting points.
lH-NMR-spectra were determined with a Bruker WH-90 spectrophotometer and the chemical shifts Stin ppm) with tetramethylsilane as reference.
Mass spectra are determined on a Varian Mat CH5 10 spectrometer or on a Mat 90 (Finnigan Mat, San José, U.S.A.).
Histamine H2-activity was determined on the right-side atrium o~ the guinea pig as described by G.J. Sterk et al in Eur.J.Med. Chem.,l9, p. 545-550 (1984).
- Histamine H2-binding was determined as described by 15 G.J. Sterk et al in Agents Actions 18, 231 (1986).
- Histamine Hl-activities were determined on the guinea-pig ileum as described by Emmett et al in J.Med.Chem. 25, 116B-1174 (1982).
- Histamine H3-activities were determined on the guinea-pig 20 ileum as described by G.J. Menkveld and H. Timmerman in Eur.J.Pharmacol. 186, 343-347 (1990). , ' `' .` '~' ''; .". -:- .
'' `

. : : -,:

207417~
WO9l/l~56 -;"'''~`~i,' PCT/NL9lt~07 E~ample 6-bromo-Z-hexanone (6a) 6-~romo-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 10 with vigorous stirring until circa 60C. After the mild exothermal reaction beginning at circa 50C, 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 collect~d 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 (l.00 mole) of the crude 2-methyl-3-carbethoxy-5,6-dihydro-pyrane together with 140 ml of concentrated aqueous HBr-solution (48%) is refluxed with vigorous stirring for 3 hours, and a violent evolution ~f carbondioxide ~as 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 denineralized water ~ ' , ' .
. . .
' ' . . :

207~175 ~ ~
O91/l~56 PCT/NL91/~W~7 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%.
30iling point 102-106C/18 mm Hg. Reference:(Chem.Abstr., 65, P 20151d).
94-98C/12 mm Hg.
Mass spectrum M/Z (intensity in %). 180(0.14): 178(0.11);
137(6.3); 99 (100).
H-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., tri~let (J=6.8 Hz), 2H.
ExamDle 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., 58j 5659 b (1963) and such as described in Dutch patent application ~ i :
8800998, April 18,1988.
Melting point 108.5-110C (Reference: H.Irai et al. ,111-113C).
H-NMR (CDCl3j: 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.
~ .
The 5-phthalimido-2-pentanone (7a) is prepared according to Dutch patent application 8800998, April 18,1988.
Yield 53%

- . .: : : - ~ ~

2 ~ 7 ~
.,, ...,,, ~,.

Melt:ing point 72-74C.
H-NMR (CDC13): 1.89-2.12 ppm., multiplet, 2H; 2.15 ppm., sin~let, 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 (7 b) is prepared as described for the 5-phthalimido-2-pentanone (7 a) in Dutch patent application 8800998, April 18,1988.
Yield 80%, viscous oil.
H=NMR (CDC13): 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-~romo- W -phthalimido-Z-alkanones (8) __ _ General process:
To a solution of 0.5 mole of an appropriate C~-phthal-imido-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 temperat-ure for circa 2 hours. Subsequently there is added circa 100 ml chloroform and 500 ml of demineralized water, there-after it is stirred for -30 minutes. The water phase is subsequently removed and the organic phase is washed with ' .. .. .
.
.

~`. ' ` ~

~-,WO9l/l~56 2 0 7 417 ~ PCT/NL91/~07 _ g _ , .

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-( ~ -phthalimidoalkyl)thiazoles (25).
Thus there were obtained:
a. 3-Bromo-5-Dhthalimido-2-Dentanone (8a) _____ _ ___ yield 95%, from 5-phthalimido-2-pentanone (7b).
H-NMR (CDC13): 2.10-2.59 ppm., multiplet, 2H; 2.40 ppm., 10 singlet, 3H; 3.82 ppm., triplet (J=6.3 HZ), 2H; 4.34 ppm., triplet (J=7.5 Hz), lH; 7.69 ppm., multiplet, 4H.
b. 3-Bromo-6-Dhthalimido-2-hexanone (8b) ___ ____ , yield 93%,from 6-phthalimido-2-hexanone (7c).
H-NMR (CDCl3): 1.74-2.22 ppm, multlplet, 4H; 2.36 ppm., 15 singlet, 3H; 3,46-3.90 ppm., multiplet, 2H; 4.36 ppm., triplet, (J=7.2 Hz), lH, 7.60-7.95 ppm., multiplet, 4H.
Example IV
5-( ~ -Dhthalimidoalkvl General process:
To a solution of 0.2 mole of a crude 3-bromo-~Lphthal-imido-2-alkanone (8 ) in circa 100 ml of anhydrous dimethyl-formamide 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 l -.. . . . . , ,, ., , , .- ., ~ , - . . .: . . -- , ,, ., - : .

2 0 7 417 5 .~ . , PCT/NL91/~07 ~`

--10 -- , the exothermal reaction the temperature may rise to circa 100C, there is heated at circa 100C 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 3~ minutes the precipl~te 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 (9a) -yield 50%, from 3-bromo-5-phthalimido-2-pentanone ~(8a) and thioureum.
H-NMR (D6-DM50): 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 (9b) Yield 51%, from 3-bromo-6-phthalimido-2-hexanône (8b) and thioureum.
H-NMR (D6-DMS0): 1.61-2.04 ppm., multiplet, 2H, 2.15 ppmO, 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 207.4-210.6C.
H-NMR (D6-DMS0): 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 singlet, 2H.

. ... . . .

.

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~ 091/1~6 2 0 7 4 ~ 7 ~ PCT/NLg1tO~7 Example V
~- or 5-(w-aminoalkyl)thiazoles ~10) ___ ____ __ General process:
A solution of 0.1 mole of an appropriate ~-phthalimido-alkylthiazole hydrobromide ( 9) in circa 400 ml of anhydrous methanol is refluxed with 0.2 mole of an 80%-aqueous hydra-zine-hydrate solution for 5 hours. After cooling in ice the crystallized phthalhydrazine is filtered ~ff 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 aàded, 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:
, .

- . -2 0 7 4 i 7 ~ r~ r WO9l/1WS6i PCT/NL91/~0 i ' a._2~amino-5-(2-aminoethyl)-4-methylthiazole dihydrochloride (lOa) Yield 82%, from 2-amino-5-(2-phthalimidoethyl)-4-methyl-thiazole hydrobromide ( 9 a).
H-NMR (D6-DMS0): 2.19 ppm., singlet, 3H; 2.82-3.07 ppm.
broad singlet, 4H; 8.34 ppm., broad singlet, 3H; 9.32 ppm., 3 broad singlet, 2H.
Mass spectrum M/Z (intensity in %): 157(5.0); 141(3.8);
127(5.0); 114(8.3).
10 M+ = 157.06S (calculated for C6H11N3S: 157-067) b. 2-amino-5-(3-aminopropyl)-a-methylthiazole dihydro-chloride (lOb). Yield 90%, from 2-amino-5-(3-phthalimido-_ propyl)-4-methylthiazole hydrobromide (g b).
H-NMR (D6-DMS0): 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 (intensity in %): 171(28.9); 154(75.1);
127(100); 115(9.7).
M = 171.080 (calculated for C7H13N3S: 171.083).

' ~' '., . : - . ...................... .. . . . .

~ - : :

~,NO 91/10656 1~ 2 0 7 417 5 pCriNL9l/oooo7 Table I Histamine H2-activity and binding of some 5- I~- amtnoaIkyl ) thiazoles pD~+S.E pKJ lS.E
nr. compound (g.p. right at~ium) lg p cortex) ~Hz 10 a ~ ~ 6,30 ~0,04 5,30 ~ 0,08 NH~ -~,H2 5,2'0,1 NH2 . - ' ' ' ' '- ' . ' ~= ~ '' .
histamineHN~N 6,10 ' 0,06 4,16 ' 0,08 . .
: . . . ; -'.............. : ' I :

- ~ , .. . .
.~ . . .

Claims (10)

CLAIMS:
1. .omega.-Aminoalkylthiazole, characterized in that a substituted 4- or 5-(.omega.-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 .omega.-aminoalkylthiazole, characterized in that one prepares a 5-(.omega.-aminoalkyl)thiazole derivative with formula 1 as described in claim 1 by ring closure of a 3-bromo-.omega.-phthalimidoalkan-2-one (8) with thiou-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 .omega.-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 disea-ses whether or not accompanied by heart failure or for the treatment of allergic disorders.
7. A process for the preparation of 3-bromo-.omega.-phthalimido-alkan-2-ones characterized by selective bromination with bromine of the corresponding .omega.-phthalimidoalkan-2-ones.
8. A process for the preparation of 5-(.omega.-phthalimidoalkyl)-4-alkylthiazoles characterized by ring closure of a 3-bromo-.omega.-phthalimidoalkan-2-one with thiourea in dimethylformamide under mild conditions.
9. 3-Bromo-.omega.-phthalimidoalkan-2-ones.
10. 5-(.omega.-phthalimidoalkyl)4-alkylthiazoles.
CA002074175A 1990-01-19 1991-01-18 Thiazole derivatives Abandoned CA2074175A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NL9000132 1990-01-19
NL9000132A NL9000132A (en) 1990-01-19 1990-01-19 NEW THIAZOLE DERIVATIVES.

Publications (1)

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CA2074175A1 true CA2074175A1 (en) 1991-07-20

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CA002074180A Abandoned CA2074180A1 (en) 1990-01-19 1991-01-18 Thiazole derivatives
CA002074175A Abandoned CA2074175A1 (en) 1990-01-19 1991-01-18 Thiazole derivatives

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CA002074180A Abandoned CA2074180A1 (en) 1990-01-19 1991-01-18 Thiazole derivatives

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JP (2) JPH05503096A (en)
AU (2) AU7058191A (en)
CA (2) CA2074180A1 (en)
IE (2) IE910172A1 (en)
IL (2) IL96997A0 (en)
NL (1) NL9000132A (en)
WO (2) WO1991010656A1 (en)
ZA (2) ZA91418B (en)

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US7304086B2 (en) * 2004-02-05 2007-12-04 Probiodrug Ag Inhibitors of glutaminyl cyclase

Family Cites Families (7)

* Cited by examiner, † Cited by third party
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.

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EP0511271A1 (en) 1992-11-04
WO1991010656A1 (en) 1991-07-25
IE910171A1 (en) 1991-07-31
IL96997A0 (en) 1992-03-29
IL96998A0 (en) 1992-03-29
IE910172A1 (en) 1991-07-31
CA2074180A1 (en) 1991-07-20
ZA91419B (en) 1991-10-30
EP0511270A1 (en) 1992-11-04
JPH05503096A (en) 1993-05-27
WO1991010657A1 (en) 1991-07-25
AU7058191A (en) 1991-08-05
NL9000132A (en) 1991-08-16
ZA91418B (en) 1991-10-30
JPH05503694A (en) 1993-06-17
AU7064491A (en) 1991-08-05

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