US3907800A - Derivatives of spiro-{8 piperidine-4{40 :6-(3,2-a)-thiazolopyrimidine{9 - Google Patents

Derivatives of spiro-{8 piperidine-4{40 :6-(3,2-a)-thiazolopyrimidine{9 Download PDF

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US3907800A
US3907800A US385816A US38581673A US3907800A US 3907800 A US3907800 A US 3907800A US 385816 A US385816 A US 385816A US 38581673 A US38581673 A US 38581673A US 3907800 A US3907800 A US 3907800A
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spiro
piperidine
thiazolopyrimidine
hydroxy
hexahydro
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Szarvasi Etienne
Festal Didier
Grand Marcel
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Merck Sante SAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Definitions

  • the invention also includes within its scope the free bases of the salts represented by formula I.
  • the compounds of formula I isolated in the form of salts, can be neutralised and isolated in the form of free bases, which can-then be transformed into other salts with an appropriate acid.
  • the compounds of formula I in which R is a double bond in the 3-2 position can be isolated in the form of the free base which can be converted into a salt.
  • phamacologically preferred compounds of the invention are the pharmaceutically acceptable salts of the compounds:
  • the spiro-[4':6-piperidine-3-hydroxy-3-aryl- 2,3,4,5,6,7-hexahydro-(3,2-a)-thiazolopyrimidines] of the invention i.e. the compounds of formula I in which R, is a hydroxy radical, can be prepared by reacting at a temperature in the range of from ambient temperature to 50C. an a-halogenated ketone of the general formula:
  • R has the same meaning as in formula I and Y is a halogen atom, preferably bromine, in an inert solvent, for example ethylene glycol or preferably dimethylformamide.
  • the intermediate spiro compounds of formula II which are the hydrohalic acid salts of spiro[4':5- piperidineperhydro-l,3-pyrimidine-2-thiones] can be prepared by reacting a substituted 4,4-bisaminomethyl-piperidine represented by the general formula;
  • R has the same meaning as in formula I, with carbon disulphide and treating the resulting condensation product with a hydrohalic acid to obtain the required compound of formula II.
  • the compounds of formula 111 can be prepared by reduction of dinitriles of the general formula:
  • R has the same meaning as in formula I.
  • the reduction may be effected by catalytic hydrogenation or by the use of a reducing agent such as lithium aluminium hydride.
  • the dinitriles of formula IV can be prepared by the condensation of a chlorinated base represented by the general formula:
  • an acid addition salt thereof for example a hydrohalic acid salt, wherein R has the same meaning as in formula I, with malonitrile in the presence of an acid acceptor, for example an alkali metal carbonate such as potassium carbonate, and in an aprotic solvent, preferably hexamethyl phosphorotriamide (I-IMPT).
  • an acid acceptor for example an alkali metal carbonate such as potassium carbonate
  • an aprotic solvent preferably hexamethyl phosphorotriamide (I-IMPT).
  • heterocyclic spiro compounds of formula I will normally be employed as therapeutic agents in the form of a pharmaceutical composition comprising as an essential active ingredient a compound of formula I, in association with at least one pharmaceutical carrier or excipient therefor.
  • the composition will advantageously be a dosage unit form appropriate to the required mode of administration.
  • the composition may be in the form of a tablet or capsule.
  • FIGS. 1-35 of the Drawings illustrate various relevant structural formulae.
  • a dropping funnel and a reflux condenser are placed 75.9 g. (0.55 mole) of potassium carbonate and 1 10 ml. of freshly distilled hexamethyl phosphorotriamide (l-IMPT); through the dropping funnel is added dropwise and at ambient temperature, and while stirring, a solution of 33 g. (0.5 mole) of malononitrile in 150 ml. of HMPT.
  • the resulting mixture is heated at 60- to 65C. for 2 hours and then, at the same temperature, are added 99 g. (0.5 mole) of bis-2-chloroethyl)- n-butylamine; the heating is maintained for 3 hours, the
  • I-IMPT is evaporated under reduced pressure, the solid residue is taken up in water and the solution is extracted with ether; the ethereal layer is washed with water, dried over sodium sulphate, filtered, the ether is evaporated and the residual oil is distilled. In a yield of 49% (theoretical yield: 95.7 g. a colourless liquid having a b.p. 0.25 mm of 82C. is obtained.
  • a fluid-tight and dry reactor provided with a reflux condenser, an agitator and a dropping funnel, are placed 3,000 ml. of dry ether and 32 g. (0.84 mole) of LiA1H a solution of 54 g. (0.28 mole) of l-n-butyl 4,4-bis-cyano-piperidine in 300 ml. of ether is added dropwise so as to maintain a gentle reflux. The mixture is then heated under reflux for 4 hours; the mixture is cooled and there are added dropwise 200 ml. of caustic soda solution and 50 ml.
  • Spiro[ l '-n-butyl-4:5- piperidinel ,3-perhydropyrimidine-2-thione hydrobromide can beprepared by replacing the hydrochloric acid by hydrob'romic acid. In a quantitative yield, there is obtained a product having a melting point of 290-293C.
  • the product shows with the mouse a lethal dose LD 1.440 mgJkg. P.O. (per 0s) and 17 mg./kg. l.V. (intravenous).
  • the activity coefficients are expressed by reference to two standards: y
  • Phenergan l-( 2-dimethylaminopropyl)- phenthiazine in the test with adenosine diphosphate (A.D.P.)
  • the product has the coefficient 9. It is not thymo-analeptic, but platelet anti-aggregant.
  • Example 1(a) a. 1-ben2yl-4,4-bis-cyano-piperidine
  • the product is obtained starting with 322.3 g. (1.2 moles) of the hydrochloride of bis-(2-chloroethyl)-benzylamine (m.p. l47148C.).
  • a colourless liquid is isolated by distillation under reduced pressure, hp. 0.5 0.6 123l26C. Yield: 181 g. 66% (theoretical yield: 270 g.).
  • Infra-red pC N 2250 cm.
  • This product is thus at the frontier of the two activities, having a not negligible thymo-analeptic efiect and is anti-aggregant in vitro.
  • Example 2(d) The required compound was prepared by the procedure described in Example 2(d) using 2,5-dimethoxyw-bromoacetophenone and spiro[1-benzyl-4:5- piperidine-l ,3- perhydropyrimidine-Z-thione]hydrobromide as prepared in Example 2(c). Yield m.p. 251-252C.
  • Pharmacology LD 1200 mg./kg. PD. and 41 mg./kg. I.V.
  • Collagen 342 Ptosis to Reserpine 5 This product is anti-aggregant, thymoanaleptic effect.
  • Example 2( d) The required compound was prepared by the procedure described in Example 2( d) starting with 3,4- dichloro-w-bromo acetophenone and spiro[1'-benzy1- 4:5-piperidine-1,3- perhydropyrimidine-2-thione]hydrobromide as pre-' pared in Example 2(c). Yield 97%, mp. 260262C. 1
  • Example 2(d) The required compound was prepared by the procedure described in Example 2(d) starting from 2-wbromoacetyl-S,6,7,8-tetrahydronaphthalene and spiro- [l '-benzyl-4:5-piperidine-l ,3-perhydropyrimidine-2- thione]hydrobromide as prepared in Example 2(c). Yield 94%, mp. 240-241C.; after being recrystallised from a mixture of methanol and water (1:5), m.p.
  • Infra-red 'y N11 3360 cm" to 3270 cml.
  • the low coefficient in the test with collagen indicates that it is a product which is practically deprived of any platelet anti-aggregant effect. On the contrary, the product is thymo-analeptic.
  • the required compound was prepared by the procedure described in Example 6, using in step (d) 2,5- dimethoxy-w-bromoacetophenone in place of the 3,4- dichloro-w-bromoacetophenone. Yield: quantitative, m.p. l94-l95C.; after recrystallisation from ethanol, m.p. 197-l99C.
  • Pharmacology LD (mouse) 680 mg./kg. P.O. and 38 ml./kg. l.V. A.D.P. 58
  • Pharmacology LD (mouse) 900 mg./kg. P.O.
  • Collagen 300 Ptosis 12 The product is a platelet anti-aggregant.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A novel class of heterocyclic spiro compounds is disclosed the members of which possess utility in the therapeutic field, particularly as thymo-analeptics or platelet anti-aggregants. The compounds are derivatives of spiro-(piperidine-4'':6-(3,2-a)thiazolopyrimidine).

Description

United States Patent 1191 Etienne et al.
[ Sept. 23, 1975 DERIVATIVES OF SPlRO-[PlPERlDINE-4 ':6-(3,2-A)- THIAZOLOPYRIMIDINE] [75] Inventors: Szarvasi Etienne,
Charbonnieres-les'Bains; Festal Didier, Ecully; Grand Marcel, Bron,
all of France [73] Assignee: Lipha-Lyonnaise Industrielle Pharmaceutique, Lyon, France [22] Filed: Aug. 6, 1973 21 Appl. No.1 385,816
[30] Foreign Application Priority Data Aug. 9, 1972 France 72.28747 52 US. (:1 260/256.5 R; 260/293.51; 260/293.75; 260/293.78; 260/293.87; 260/570.9; 260/583 G; 424/251 Primary ExaminerRichard J. Gallagher Attorney, Agent, or Firm-Browdy and Neimark [57] ABSTRACT A novel class of heterocyclic spiro compounds is disclosed the members of which possess utility in the therapeutic field, particularly as thymo-analeptics or platelet anti-aggregants. The compounds are derivatives of spiro-[piperidine-4 :6-(3 ,2-a)- thiazolopyrimidine].
11 Claims, 35 Drawing Figures US Patent Sept. 23,1975 Sheet 2 of4 3,907,800
US Patent Sept. 23,1975 Sheet 3 of4 3,907,800
G) H S OH OCH ZBr 5 DERivATiv soF SPIRO-[PIPERIDINE-4:6-(3,2-a)- THIAZOLOPYRIMIDINE] FIELD OF THE INVENTION. Y
Y BACKGROUND OF THE INVENTION For several years compounds having very varied molecular structures have been proposed for inhibiting the aggregation of blood platelets in human beings. Recently, Elslage'r (J. of Med. Chem. 1971, page 1759) has described the 5,lO-dihydro-3-phenyl[3,2-b]- thiazolo-2,4-diazepi'nes as being active for this purpose. The activity varies with the nature and position of the substituent on the aromatic nucleus which is in the 3- position of the thiazolodiazepine. I
The preparation of the intermediate diamine '(oxylene-m,w-diamine) from the phthalazine is' a difiicult operation, which can be a serious obstacle to the process being used on an industrial scale.
on the other hand, Sharpe (J. of Med. Chem. 1971,
page 977) has described a series of phenacylthio-' imidazolines partially cyclised into [2H]-5,6-dihydro- 3-hydroxy-3-aryl-[2,l-b]-imidazothiazoles, as being thymo-analeptics.
SUMMARY OF THE INVENTION It has been found according to the present invention that a new class of compounds consisting of heterocyclic spiro compounds has thymo-analeptic or "platelet anti-aggregant activities depending on the nature of the substituents introduced into the heterocyclic nucleus. Another advantage of thisclass of compounds resides in the low toxicity of the compounds compared to that of the known substances having such activities.
DETAILED DESCRIPTION or THE INVENTION The class of compounds withwhich the present invention is concerned comprises the salts represented by the general formula? r Xis a halogen atom or a pharmaceutically acceptable acid radical, for example an oxalyl radical:
The invention also includes within its scope the free bases of the salts represented by formula I.
The compounds of formula I, isolated in the form of salts, can be neutralised and isolated in the form of free bases, which can-then be transformed into other salts with an appropriate acid. The compounds of formula I in which R is a double bond in the 3-2 position can be isolated in the form of the free base which can be converted into a salt.
5,6,7,8-tetrahydro-2-naphthyl, and the corresponding free bases of said salts.
Examples of phamacologically preferred compounds of the invention are the pharmaceutically acceptable salts of the compounds:
spiro[ l-n-butyl-4' :6-piperidine-3-( 2,5-
dimethoxypheny)-3 -hydroxy-2 ,3 ,4,5 ,6,7- hexahydro[3,2-a]-thiazolopyrimidine] spiro[ l'-benzyl-4':6-piperidine-3-hydroxy-3-( 2- naphthyl)-2,3,4,5,6,7-hexahydro-[3,2-a]- thiazolopyrimidine] spiro[ l '-benzyl-4' :6-piperidine-3-(2,5e
dimethoxy pheny-)-3-hydroxy-2,3,4,5,6,7-hexahydro- [3 ,2-a l thiazolopyrimidine] spiro[ l'-benzyl-4:6-piperidine-(3,4-
dichloro'pheny- -3-hydroxy-2,3;4,5,6,7-hexahydro-[3,2-a]- thiazolopyrimidine] spiro[ l -benzyl-4':6-piperidine-3-hydroxy-3- J 1 (5,6,7,8-tetrahydro-2-naphthyl)-2,3,4,5,6,7-
- hexahydro-[3,2-a]-thiazolopyrimidine],
spiro[ l -n-octyl-4':6-piperidine 3-( 3,4
dichloropheny- )-3-hydroxy-2,3,4,5,6,7- hexahydro[3,2-a] t hiazolopyrimidine],
spiro[ l '-n-octyl-4':6-piperidine-3-hydroxy-3- (2,5-dimethoxyphenyl)-2,3,4,5,6,7- .hexahydro[3,2-a]-thiazolopyrimidine],
spiro[ l -benzy]-4':6 piperidine-3-hydroxy-3- (2-methoxyphenyl)-2,3,4,5,6,7-hexahydro-[3,2- a]-thiazolopyrimidine]-, and
spiro[ l"-n-octyl- 4 :6-piperidine-3-hydroxy-3- (2-rnethoxyphenyl)-2,3,4,S,6,7-
hexahydro[3,2 a]-thiazolopyrimidine], and the conipoundz spiro[ l '-n-butyl- 4:6-piperidine-3-(Z-naphte.
hyl)4,5,6,7-tetrahydro-[3,2-a]-thiazolopyrimidine] and its pharmaceutically acceptable salts.
The spiro-[4':6-piperidine-3-hydroxy-3-aryl- 2,3,4,5,6,7-hexahydro-(3,2-a)-thiazolopyrimidines] of the invention, i.e. the compounds of formula I in which R, is a hydroxy radical, can be prepared by reacting at a temperature in the range of from ambient temperature to 50C. an a-halogenated ketone of the general formula:
wherein R has the same meaning as in formula I and Y is a halogen atom, preferably bromine, in an inert solvent, for example ethylene glycol or preferably dimethylformamide.
When the reaction is carried out at a temperature in the range of from 125 to 160C., preferably l50160C., the Spiro[4:6-piperidine-3-aryl-4,5,6,7- tetrahydro(3,2-a)-thiazolopyrimidines] of formula I, in which R represents a double bond in the 3,2-position of the thiazolopyrimidine, are formed.
In the latter reaction, it is preferred to use ethylene glycol as the inert solvent.
The intermediate spiro compounds of formula II, which are the hydrohalic acid salts of spiro[4':5- piperidineperhydro-l,3-pyrimidine-2-thiones] can be prepared by reacting a substituted 4,4-bisaminomethyl-piperidine represented by the general formula;
III
wherein R has the same meaning as in formula I, with carbon disulphide and treating the resulting condensation product with a hydrohalic acid to obtain the required compound of formula II.
The compounds of formula 111 can be prepared by reduction of dinitriles of the general formula:
wherein R has the same meaning as in formula I. The reduction may be effected by catalytic hydrogenation or by the use of a reducing agent such as lithium aluminium hydride.
The dinitriles of formula IV can be prepared by the condensation of a chlorinated base represented by the general formula:
or an acid addition salt thereof, for example a hydrohalic acid salt, wherein R has the same meaning as in formula I, with malonitrile in the presence of an acid acceptor, for example an alkali metal carbonate such as potassium carbonate, and in an aprotic solvent, preferably hexamethyl phosphorotriamide (I-IMPT).
The various intermediates represented by the foregoing formulae II, III, IV and V form part of the present invention, particularly the intermediates in which R is a butyl, octyl or benzyl radical.
The heterocyclic spiro compounds of formula I will normally be employed as therapeutic agents in the form of a pharmaceutical composition comprising as an essential active ingredient a compound of formula I, in association with at least one pharmaceutical carrier or excipient therefor. The composition will advantageously be a dosage unit form appropriate to the required mode of administration. For example, for oral administration the composition may be in the form of a tablet or capsule.
FIGS. 1-35 of the Drawings illustrate various relevant structural formulae.
EXAMPLES The following Examples illustrate various embodiments of the invention in a non-limiting manner.
Empirical formula: C H Br,N,0S
Molecular weight:
a. 1-n-Butyl-4,4-bis-cyano-piperidine Prepared:
i. from bis-(2-chloroethyl)-n-butylamine ii. from the hydrochloride of the above amine.
i. In a fluid-tight and dry reactor, equipped with an agitator, a dropping funnel and a reflux condenser are placed 75.9 g. (0.55 mole) of potassium carbonate and 1 10 ml. of freshly distilled hexamethyl phosphorotriamide (l-IMPT); through the dropping funnel is added dropwise and at ambient temperature, and while stirring, a solution of 33 g. (0.5 mole) of malononitrile in 150 ml. of HMPT. The resulting mixture is heated at 60- to 65C. for 2 hours and then, at the same temperature, are added 99 g. (0.5 mole) of bis-2-chloroethyl)- n-butylamine; the heating is maintained for 3 hours, the
I-IMPT is evaporated under reduced pressure, the solid residue is taken up in water and the solution is extracted with ether; the ethereal layer is washed with water, dried over sodium sulphate, filtered, the ether is evaporated and the residual oil is distilled. In a yield of 49% (theoretical yield: 95.7 g. a colourless liquid having a b.p. 0.25 mm of 82C. is obtained.
Infra-red Spectrum nitrile band at 2250 cm.
To a solution of 3.8 g. (0.02 mole) of l-n-butyl- 4,4-bis-cyano-piperidine in 100 ml. of acetone is added dropwise and while stirring a solution of 3.15 g. (0.025 mole) of oxalic acid dihydrate in 50 ml. of acetone. The acid oxalate immediately precipitates and then it is suction-filtered and dried in an oven. Yield: 5.3 g. 94.5% (theoretical yield: 5.6 g.); m.p. 173175C., this being unchanged after crystallisation in ethanol.
Acidity index Calculated 398 Found 395 Analysis:
C% H% N% 0% Calculated: 55.50 6.81 14.91 22.75 Found: 55.46 6.80 14.89
b. 4,4-bis-aminomethyll -n-butyl-piperidine Prepared by catalytic hydrogenation in the presence of Raney nickel or by reduction with lithium aluminium hydride of the 1-n-butyl-4,4-bis-cyano-piperidine as prepared in (a).
i. Hydrogenation In a 500 ml. autoclave are placed 48 g. (0.25 mole) of l-n-butyl-4,4-bis-cyano-piperidine, a solution of 8 g. of NH in 310 ml. of ethanol and g. of Raney nickel. After introducing hydrogen (120 kg/cm the resulting mixture is agitated and heated at 60-70C. for 2 hours. After heating, the ethanolic solution is filtered, the ethanol is evaporated and the residual oil is distilled. A colourless liquid is obtained which crystallises at ambient temperature. Yield: 28.4 g. 57% (theoretical yield: 49.8 g.), b.p. 0.9 l08109C; m.p. --30C.
ii. Reduction by LiAll-I,
In a fluid-tight and dry reactor, provided with a reflux condenser, an agitator and a dropping funnel, are placed 3,000 ml. of dry ether and 32 g. (0.84 mole) of LiA1H a solution of 54 g. (0.28 mole) of l-n-butyl 4,4-bis-cyano-piperidine in 300 ml. of ether is added dropwise so as to maintain a gentle reflux. The mixture is then heated under reflux for 4 hours; the mixture is cooled and there are added dropwise 200 ml. of caustic soda solution and 50 ml. of water; the ethereal layer is decanted; there are added thereto the ethereal extracts of the precipitate of formed hydroxides, followed by drying over sodium sulphate and filtering, whereupon the ether is evaporated and the residual oil is distilled. Yield: 90 g. 80% (theoretical yield: 112 g.). B.P. 109-l 10C. The product is identified in the form of a trihydrochloride monohydrate:
C, H N Cl M.W. 308.72; m.p. 219-221C.
Calculated: 515 Found 500 Analysis:
C% H% N% Cl% 0% Calculated: 40.43 9.25 12.86 32.55 4.89 Found: 40.40 9.28 12.90 32.48
c Spiro[ l -n-butyl-4:5-piperidine-l ,3-
perhydropyrimidine-Z-thione hydrochloride Empirical formula: Molecular weight: C l-I Cl N,S 277.85
To a solution of 19.3 g. (0.1 mole) of 4,4-bisaminomethyl-l-n-butyl-piperidine as prepared in (b) in 80 ml. of ethanol are added dropwise, at 60 and C., 8 g. (0.1 mole 10%) of carbon disulphide, and when the addition is completed, heating takes place on a boiling water bath for one hour, whereafter the mixture is cooled to ambient temperature and there are added thereto 12 ml. of concentrated hydrochloric acid; further heating takes place on the boiling water bath for 6 hours. After heating, the solution is cooled and the formed precipitate is suctionfiltered after adding ether; in a yield of 94.6% (theoretical yield: 27.8 g.), there are obtained 25.6 g. of solid product, m.p. 299300C.
Analysis:
C% 11% N% S% Cl% Calculated: 51.87 8.70 15.12 1 1.54 12.77 Found: 51.85 8.67 15.13 11.53 12.80
In an analogous manner, Spiro[ l '-n-butyl-4:5- piperidinel ,3-perhydropyrimidine-2-thione hydrobromide can beprepared by replacing the hydrochloric acid by hydrob'romic acid. In a quantitative yield, there is obtained a product having a melting point of 290-293C.
d. To a solution of 22 g. (0.0684 mole) of spiro[1'- n-butyl-4':5-piperidine-1 ,3-perhydropyrimidine2- thione]-hydrobromide as prepared in (c) in 200 m1. of dimethylformamide are added, at a temperature of from 50-55C., 17.7 g. (0.0684 mole) of 2,5-dimethoxy-w-bromoacetophenone in 40 m1. of dimethylformamide. On completing the addition, heating at 55C. takes place for 30 minutes. After evaporation of the solvent, washing is effected with ether. A quantitative yield of 41.2 g. of product with a melting point of 230C. is obtained. After recrystallisation from methanol, the melting point remains unchanged.
The product shows with the mouse a lethal dose LD 1.440 mgJkg. P.O. (per 0s) and 17 mg./kg. l.V. (intravenous).
Its platelet anti-aggregant effect is determined in vitro in two tests:
a. Aggregation caused by adenosine diphosphate (A.D.P.)
b. Aggregation caused by collagen. I
The activity coefficients are expressed by reference to two standards: y
a. Phenergan: l-( 2-dimethylaminopropyl)- phenthiazine in the test with adenosine diphosphate (A.D.P.)
b. Acetyl salicylic acid in the test with collagen.
These two standards are arbitrarily assigned the coefficient l.
The product described in Example 1 has the following coefficients:
a. A.D.P.
b. collagen 163.
Its thymo-analeptic effect is measured in the antagonism to the ptosis caused by Reserpine (lowering of the bottom eyelid of the animal (mouse) due to the central action of Reserpine). The coefficient 100 is attributed to the control substance lmipramime.
In this test, the product has the coefficient 9. It is not thymo-analeptic, but platelet anti-aggregant.
. EXAMPLE 2 Spiro[l '-benzyl-4:6-piperidine-3-hydroxy-3-(2- naphthyl)- 2,3,4,5,6,7-hexahydro[3,2-a]-thiazolopyrimidine]dihydrobromide Empirical formula: Molecular weight:
a. 1-ben2yl-4,4-bis-cyano-piperidine In the manner described in Example 1(a), the product is obtained starting with 322.3 g. (1.2 moles) of the hydrochloride of bis-(2-chloroethyl)-benzylamine (m.p. l47148C.). A colourless liquid is isolated by distillation under reduced pressure, hp. 0.5 0.6 123l26C. Yield: 181 g. 66% (theoretical yield: 270 g.). Infra-red pC N=2250 cm.
b. 4,4-bis-aminomethyl-l-benzyl-piperidine In the manner described in Example 1(b), the product is obtained, starting with 22.05 g. (0.1 mole) of 1- benzyl-4,4-bis-cyano-piperidine as prepared in (a), in liquid form with a b.p.0.60.9 mm 135149C. Yield: 15.4 g. 66% (theoretical yield: 23.3. g.). Infrared y NH; 3370 cm" 3290 cm Analysis: (Results obtained. on a twice-distilled sample. b.p.0.4 137C.)
C% H% N% Calculated: 72.06 9.93 18.01 Found: 72.03 9.90 18.05 Trihydrochloride monohydrate C H,,N,C1,0 M.W. 360.76
Prepared by the action of hydrochloric acid gas on the above base in solution in ethanol. m.p. 272273C. (after crystallisation in ethanol).
Analysis:
C% 11% N% C1% Calculated: 46.60 7.82 1 1.64 29.48 Found: 46.60 7.80 11.60 29.50
c. I Spiro[1'-benzyl-4:5-piperidine-l,3- perhydropyrimidine-Z-thione]hydrobromide I Empirical formula: Molecular weight:
C,,H,,BrN,s 356.33
1 Starting from 4,4-bis-aminomethyl-lbenzylpiperidine as prepared in (b) above, and carrying out the cyclisation in the manner described in Example l(c) using 40% HBr, there is obtained in a quantitative yield a solid having a melting poing of 259261C. (methanol/water).
C% 11% N% 8% Br% Calculated: 50.56 6.23 1 1.80 9.00 22.44 Found: 50.60 6.26 1 1.77 8.98 22.42
d. To 12.5 g. (0.035 mole) of spiro[1'benzyl-4:5- piperidinel ,3-perhydropyrimidine-2-thionelhydrobromide as prepared in (c) in suspension in 100 ml. of dimethylformamide are added, at a temperature of from 50-55C., 8.7 (0.035 mole) of a w-bromoacetonaphthone-2 in 50 ml. of dimethylformamide. After heating for a few minutes, a limpid solution is formed and then a white solid precipitate. After heating for 30 minutes at 55C., filtering with suction, washing with ether and drying, there is obtained in a yield of 89% (theoretical yield: 21.2 g.), 18.9 g. of solid product,
Collagen 67 Ptosis to Reserpine 101 Active close (AD 57 mg./kg.
This product is thus at the frontier of the two activities, having a not negligible thymo-analeptic efiect and is anti-aggregant in vitro.
EXAMPLE 3 Spiro[ 1 '-benzyl-4':6-piperidine-3-( 2,5-dimethoxyphenyl )-3- hydroxy-2,3,4,5,6,7-hexahydro-[3,2-a]- thiazolopyrimidine -dihydrobromide Empirical formula: c u arm ms Molecular weight:
The required compound was prepared by the procedure described in Example 2(d) using 2,5-dimethoxyw-bromoacetophenone and spiro[1-benzyl-4:5- piperidine-l ,3- perhydropyrimidine-Z-thione]hydrobromide as prepared in Example 2(c). Yield m.p. 251-252C.
After recrystallisation from alcohol/water (6:1),the
melting point was unchanged. I
Analysis:
C% H% N% l 5% Br% Calculated: 48.78 5.40 6.83 5.21 25.97 Found: 48.75 5.38. 6.80 5.19 26.00
Pharmacology LD (mouse) 1200 mg./kg. PD. and 41 mg./kg. I.V.
A.D.P. 27
Collagen 342 Ptosis to Reserpine 5. This product is anti-aggregant, thymoanaleptic effect.
EXAMPLE 4..
Spiro[ 1 '-benzyl-4:6-piperidine-(3,4-dichlorophenyl)- -3-hydroxy-2 ,3 ,4,5 ,6 ,7-hexahydro-[3 ,2-a]- thiazolopyrimidine]-dihydrobromide without any Empirical formula: C H B CLN OS Molecular weight: 624.28.
The required compound was prepared by the procedure described in Example 2( d) starting with 3,4- dichloro-w-bromo acetophenone and spiro[1'-benzy1- 4:5-piperidine-1,3- perhydropyrimidine-2-thione]hydrobromide as pre-' pared in Example 2(c). Yield 97%, mp. 260262C. 1
After recrystallisation from water, m.p. was 264-266C. 1
-2-naphthyl)-2,3,4,5,6,7-hexahydro-[3,2-a]- thiazolopyrimidine]dihydrobromide Molecular weight:
Empirical formula: C,,H,,N,S Br,0
The required compound was prepared by the procedure described in Example 2(d) starting from 2-wbromoacetyl-S,6,7,8-tetrahydronaphthalene and spiro- [l '-benzyl-4:5-piperidine-l ,3-perhydropyrimidine-2- thione]hydrobromide as prepared in Example 2(c). Yield 94%, mp. 240-241C.; after being recrystallised from a mixture of methanol and water (1:5), m.p.
l kfi C% 11% N% 3% Br% Calculated: 53.20 5 .79 6.89 5.26 26.23 Found: 53.24 5.81 6.89 5.19 26.20
Pharmacology 1.1 (mouse) 3200 mg./kg. Ptosis to Reserpine EXAMPLE 6 Spiro[ 1 '-n-octyl-4':6-piperidine-3-( 3 4- dichloropheny1)-3- hydroxy-2,3,4,5,6,7-hexahydro-[3,2-a]- thiazolopyrimidine]-dihydrobromide Molecular weight:
Empirical formula: C,.H,-,Br=Cl,OS
a. 1-n-octyl-4,4-bis-cyano-piperidine In a fluid-tight and dry reactor, flushed with a stream of dry nitrogen, are placed 18.24 g. (0.132 mole) of potassium carbonate and 50 ml. of freshly distilled hexamethyl phosphorotriamide (HMPT); into the resulting suspension is introduced dropwise (in minutes) and at ambient temperature, a solution of 7.8 g. (0.118 mole) of malononitrile in 80 ml. of HMPT. The mixture is then heated between 60 and 65C. for 2 hours, and
thereafter 30 g. (0.1 18 mole) of bis-(2-chloroethyl)-noctylamine are introduced at such a speed that the temperature remains between 60 and 65C., and the heating at this temperature is continued for 3 hours; after 4 heating, the HMPT is distilled off under reduced pressure until there is obtained a viscous residue which is takenup in water and ether; the aqueous layer is once again extracted with ether, the ethereal extracts are copiously washed with water, dried over sodium sulphate, filtered, and then the ether is evaporated and the residual oil is distilled to give the required product, b.p. 1 l7-l19C. Yield: 23 g. =79 (theoretical yield 29.18 g.).
Chromatography in vapour phase on XE (220C.) in CHCl single product.
Infra-red: C N 2250 cm Analysis:
C% H% N% Calculated: 72.82 1019 16.99 Found: 10.16 17.00
b; 4,4-bis-aminomethyl- 1 -n-octyl-piperidine In a fluid-tight and dry reactor, flushed with a stream of dry nitrogen, are placed 3000 m1. of anhydrous ether and 25.6 g. (0.675 mole) of lithium aluminium hydride. Introduced dropwise into this suspension (in about one hour) so as to maintain a gentle reflux of the ether is place on a boiling water bath for 6 hours, followed by a solution of 56 g. (0.225 mole) of l-n-octyl-4,4-biscyano-piperidine (prepared as in (a) above) in 250 ml.
of ether, whereafter the mixture is heated under reflux for 4 hours; after heating, the aluminium and lithium complex is hydrolysed by adding 260 ml. of 30% caus- 5 tic soda solution and 100 ml. of water, whereafter the ethereal layer is decanted, washed over sodium sulphate, filtered, and then the ether is evaporated and the residual oil is distilled. A colourless liquid is isolated, which crystallises after standing at ambient temperature, b.p. 175-l 76C. Yield 36.6 g. 64% (theoretical yield 57.5). Melting point 30C. Chromatography in vapour phase: on XE 60 (220C.): single product.
Infra-red: 'y N11 3360 cm" to 3270 cml.
It is analysed in the form of the trihydrochloride prepared by the action of hydrogen chloride on the above base in solution in ethanol between 0 and 10C. Very hygroscopic white solid. Melting point 228230C. (decomposition). (After being dried at 140C. under reduced pressure).
Analysis: (Results after drying the sample at 100C. under reduced pressure) C% H% N% Cl% Calculated: 49.38 9.94 1 1.52 29.16 Found: 49.40 9.92 1 1.54 29.18
c. Spiro[ 1 -n-octyl-4:5-piperidine-1,3-perhydropyrimidine-Z-thione]hydrochloride Empirical formula: Molecular weight: C ,l-l;,ClN,S 333.94
In a fluid-tight and dry reactor is placed a solution of 45 g. (0.176 mole) of 4,4-bis-aminomethyl-l-noctylpiperidine (prepared as in (b) above) in 150 ml. of ethanol. Into the agitated solution are introduced dropwise over 30 minutes, 13.7 g. (0.18 mole) of carbon disulphide in the following manner: 3 to 4 g. are added at ambient temperature and the remaining part is added between 60 and 65C. After adding the carbon disulphide, the mixture is heated on a boiling water bath for one hour, whereafter there are added thereto, while cooling so as to keep the temperature at 25C., 18.5 ml. of 36% hydrochloric acid. Heating then takes cooling, whereafter the precipitate obtained is suctionso filtered, washed with ether and dried at 120C. under reduced pressure. Melting point 276-278C. Yield: 55.6 g. 95% (theoretical yield: 58.6 g.).
Analysis: (Results obtained after drying at 110C.
under reduced pressure) C% 11% N% s% Cl% Calculated: 57.54 9.66 12.58 9.60 10.61
Found: 57.50 9.69 12.55 9.60 10.63
in 230 ml. of dimethylformamide, are added at the temperature of 55C. and over a period of 5 minutes, 6.7
Analysis:
0% 11% 19% 5% c1% Br% Calculated: 44.59 5.77 6.50 4.96 10.97 24.73 Found: 44.60 5.80 6.46 5.00 10.96 24.72
PHARMACOLOGY LD (mouse) 3200 mg./kg. P.O. A.D.P. =22
Collagen 36 Ptosis to Reserpine AD 21.7 mg./kg.
The low coefficient in the test with collagen indicates that it is a product which is practically deprived of any platelet anti-aggregant effect. On the contrary, the product is thymo-analeptic.
' EXAMPLE 7 Spiro[ 1 '-n-butyl-4':6-piperidine-3-(2-naphthyl)- 4,5,6,7-tetrahydro-[3,2-a]-thiazolopyrimidine] Molecular weight:
Empirical formula: C H,,N,S
To a solution of 22g. (0.684 mole) of spiro[1-nbutyl-4 :5-piperidine-1 ,3-perhydropyrimidine-2- thionelhydrobromide (prepared as described in Example l(c)) in ml. of ethylene glycol is added at C. and while stirring a solution of 17.1 g. (0.0684 mole) of m-bromoacetonaphthone-Z in 50 ml. of diethylene glycol dimethyl ether.
After heating the mixture to boiling point for one hour,.the volatile products are evaporated under reduced pressure; after dissolving the residual oil in the minimum quantity of isopropanol and adding ether, a hydroscopic, beige solid is isolated, and this is dissolved in 250 ml. of water; the solution is made alkaline by adding 30% caustic solution; it is extracted with ether, dried over sodium sulphate, filtered, evaporated to dryness and a pasty solid is isolated, which crystallises from a dispersion in hexane. Yield 14.9 g. 56%
(theoretical yield: 26.8 g.); m.p. 92-94C.; after being recrystallised from diisopropyl ether, m..p. 9 4-96C.
Analysis: I
p C% H% N% 5% Calculated: 73.21 7.47 10.73 8.19 Found: 1 73.65 7.42 10.81 8.24
Acid dioxalate: C H N SO m.w. 571.62
. y 13 Yield: quantitative, l 92- l94C. (decomposition). After being recrystallised from methanol, m.p. l93-l95C. (decomposition).
Calculated: 384 i Found: 380
Analysisz k Calculated: Found:
Pharmacology A.D.P. Collagen =70 Ptosis to Reserpine 6] EXAMPLE 8 Spiro[ l -n-octyl-4' :o-piperidine-3-h ydroxy-3-(2,5-
'dimethoxy pheny- )-2,3 ,4,5 ,6,7-hexahydro-[3,2-a]-thiazolopyrimidine]- dihydrobromide Molecular weight: 636.72
Empirical formula: c,,11 N,sBr,o,
The required compound was prepared by the procedure described in Example 6, using in step (d) 2,5- dimethoxy-w-bromoacetophenone in place of the 3,4- dichloro-w-bromoacetophenone. Yield: quantitative, m.p. l94-l95C.; after recrystallisation from ethanol, m.p. 197-l99C.
Analysis:
C% 11% N% 8% Br% Calculated: 49.04 6.80 6.59 5.03 25.10 Found: 49.00 6.84 6.55 5.07 25.17
Pharmacology LD (mouse) 680 mg./kg. P.O. and 38 ml./kg. l.V. A.D.P. 58
Collagen 923 Ptosis 33 EXAMPLE 9 Spiro[ l-benzyl-4':6-piperidine-3-hydroxy-3-(2- methoryphenyl)-2,3,4,5,6,7-hexahydro-[ 3,2-a]- thiazolopyrimidine]dihydrobromide Empirical formula: u at a 'z z LD (mouse) ="580 mg./ k g and 87.5 mg./kg.
Analysis:
- c% 11% N% 5% Br% Calculated: 49.23 5.34 7.18 5.48 27.00 Found: 49.25 5.34 7.21 5.51 27.-38
Pharmacology LD (mouse)= 380 mg./kg. PD. and 37 mg./kg. [.V. A.D.P. 51
Collagen 341 Ptosis 27.
EXAMPLE 10 Spiro[ l '-n-octyl-4':6-piperidine-3-hydroxy-3-(2- methoxyphenyl)- 2,3 ,4,5,6,7-hexahydro-[3,2-a]-thiazolopyrimidir1e]- dihydrobromide Empirical formula: u n J z Molecular weight:
0% 11% N% 5% Br% Calculated: 49.42 6.80 6.92 5.28 26.31 Found: 49.38 6.84 6.90 5.26 26.28
Pharmacology LD (mouse) 900 mg./kg. P.O.
A.D.P. 22
Collagen 300 Ptosis 12 The product is a platelet anti-aggregant.
We claim:
1. A compound selected from the group consisting of pharmaceutically acceptable salts of spiro[ ln-butyl-4' :6-piperidine-3-( 2,5-dimethoxyphenyl 3-hydroxy-,3,4,5,6,7-hexahydro-[3,2-a]- thiazolopyrimidine];
pharmaceutically acceptable salts of spiro[ l benzyl-4':6-piperidine-3-hydroxy-3-hydroxy-3-( 2- naphthyl)-2,3,4,5,6,7- hexahydro-[ 3 ,2-a] -thiazolopyrimidine];
pharmaceutically acceptable salts of spiro[ 1'- benzyl-4:6-piperidine-3-(2,S-dimethoxyphenyl)- 3-hydroxy-2,3,4,5,6,7-hexahydro-[3,2-a]- thiazolopyrimidine pharmaceutically acceptable salts of spiro[ l benzyl-4':6-piperidine-(3,4-dichlorophenyl)-3- hydroxy- 1 ,5,6,7-hexahydro-[3,2- thiazolopyrimidine];

Claims (11)

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF PHARMACEUTICALLY ACCEPTABLE SALTS OF SPIRO(1''-N-BUTYL-4'':6PIPERIDINE-3-(2,5-DIMETHOXYPHENYL)-3-N-BUTYL2,3,4,5,6,7-HEXAHYDRO-(3,2-A)-THIAZOLOPYRIMIDINE), PHARMACEUTICALLY ACCEPTABLE SALTS OF SPIRO(1''-BENZYL-4'':6PIPERIDINE-3-HYDROXY-3-HYDROXY-3-(2-NAPHTHYL)2,3,4,5,6,7-HEXAHYDRO-(3,2-A)-THIAZOLOPYRIMIDINE), PHARMACEUTICALLY ACCEPTABLE SALTS OF SPIRO(1''-BENZYL-4'':6PIPERIDINE-3-(2,5-DIMETHOXYPHENYL-)-3-HYDROXY2,3,4,5,6,7-HEXAHYDRO-(3,2-A)-THIAZOLOPYRIMIDINE), PHARMACEUTICALLY ACCEPTABLE SALTS OF SPIRO(1''-BENYL-4'':6PIPERIDINE-(3,4-DICHLOROPHENYL)-3-HYDREOXY-2,3,4,5,6,7HEXAHYDRO-(3,2-A)-THIAZOLOPYRIMINDINE), PHARMACEUTICALLY ACCEPTABLE SALTS OF SPIRO(1''-BENZYL-4'':6PIPERIDINE-3-HYDROXY-3-(5,6,7,8-TETRAHYDRO-2 -NAPHTHYL)2,3,4,5,6,7-HEXAHYDRO-(3,2-A)-THIAZOLOPYRIMIDINE) PHARMACEUTICALLY ACCEPTABLE SALTS OF SPIROL(1''-N-OCTYL-4'':6 PIPERIDINE-3(3,4-DICHLOROPHENYL)-3HYDROXY2,3,4,5,6,7-HEXAHYDRO-(3,2-A) -THIAZOLOPYRIMIDINE), SPIROL(1''-N-BUTYL-4'':6-PIPERIDINE-3-(2-NAPHTHYL)-4,5,6,7-TET RAHYDRO-(3,2-A)THIAZOLOPYRIMIDINE) AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, PHARMACEUTICALLY ACCEPTABLE SALTS OF SPIRO(1''-N-OCTYL-4'':6PIPERIDINE-3-HYDROXY-3-(2,5 -DIMETHROXYPHENYL)2,3,4,5,6,7-HEXAHYDRO-(3,2-A)-THIAZOLOPYRIMIDINE), PHARMACEUTICALLY ACCEPTABLE SALTS OF SPIRO(1''-BENZYL-4'':6PIPERIDINE-3-HYDROXY-3-(2-METHOXYPHENYL -2,3,4,5,6,7HEXAHYDRO-(3,2-A)-THIAZOLOPYRIMIDINE), AND PHARMACEUTICALLY ACCEPTABLE SALTS OF SPIRO(1''-N-OCTYL-4'':6PIPERIDINE-3-HYDROXY-3-(2-METHOXYPHENYL) -2,3,4,5,6,7HEXAHYDRO-(3,2-A)-THIAZOLOPYRIMIDINE).
2. Pharmaceutically acceptable salts of spiro)1''-n-butyl-4'':6-piperidine-3-(2,5-dimethoxyphenyl)-3-hydroxy -2,3,4,5,6,7-hexahydro-(3,2-a)-thiazolopyrimidine).
3. Pharmaceutically acceptable salts of spiro(1''-benzyl-4'':6-piperidine-3-hydroxy-3-(2-naphthyl)-2,3,4,5,6,7 -hexahydro-(3,2-a)-thiazolopyrimidine).
4. Pharmaceutically acceptable salts of spiro(1''-benzyl-4'':6-piperidine-3-(2,5-dimethoxyphenyl)-3-hydroxy -2,3,4,5,6,7-hexahydro-(3,2-a)-thiazolopyrimidine).
5. Pharmaceutically acceptable salts of spiro(1''-benzyl-4'':6-piperidine-(3,4-dichlorophenyl)-3-hydroxy-2,3,4,5,6,7 -hexahydro-(3,2-a)-thiazolopyrimidine).
6. Pharmaceutically acceptable salts of spiro(1''-benzyl-4'':6-piperidine-3-hydroxy-3-(5,6,7,8-tetrahydro-2-naphthyl) -2,3,4,5,6, 7-hexahydro-(3,2-a)-thiazolopyrimidine).
7. Pharmaceutically acceptable salts of spiro(1''-n-octyl-4'':6-piperidine-3-(3,4-dichlorophenyl)-3-hydroxy -2,3,4,5,6,7-hexahydro-(3,2-a)-thiazolopyrimidine).
8. Spiro(1''-n-butyl-4'':6-piperidine-3-(2-naphthyl)-4,5,6,7-tetrahydro-(3,2-A) -thiazolopyrimidine) and pharmaceutically acceptable salts thereof.
9. Pharmaceutically acceptable salts of spiro(1''-n-octyl-4'':6-piperidine-3-hydroxy-3-(2,5-dimethoxyphenyl) -2,3,4,5,6,7-hexahydro-(3,2-a)-thiazolopyrimidine).
10. Pharmaceutically acceptable salts of spiro(1''-benzyl-4'':6-piperidine-3-hydroxy-3-(2-methoxyphenyl)-2,3,4,5,6,7 -hexahydro(3, 2-a)-thiazolopyrimidine).
11. Pharmaceutically acceptable salts of spiro(1''-n-octyl-4'':6-piperidine-3-hydroxy-3-(2-methoxyphenyl)-2,3,4,5,6,7 -hexahydro-(3,2-a)-thiazolopyrimidine).
US385816A 1972-08-09 1973-08-06 Derivatives of spiro-{8 piperidine-4{40 :6-(3,2-a)-thiazolopyrimidine{9 Expired - Lifetime US3907800A (en)

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US4489884A (en) * 1980-10-10 1984-12-25 Stedef S.A. Railroad tie cover
US5057513A (en) * 1989-05-25 1991-10-15 Fujisawa Pharmaceutical Co., Ltd. Spiro-thiazepine derivatives useful as paf antagonists

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US4880790A (en) * 1986-01-31 1989-11-14 American Cyanamid Company (Gem-heterocyclodimethanamine-N,N')platinum complexes

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US3507868A (en) * 1968-10-21 1970-04-21 Sandoz Ag Imidazo(2,1-b)thiazoles and thiazolo(3,2-a)pyrimidines
US3507869A (en) * 1969-02-27 1970-04-21 Sandoz Ag Substituted thiazoles
US3560515A (en) * 1968-08-05 1971-02-02 Parke Davis & Co New thiazolobenzodiazepine compounds and methods for their production
US3740394A (en) * 1969-07-03 1973-06-19 Seperic Morat Thiazolo and thiazino pyrimidines
US3763142A (en) * 1971-11-09 1973-10-02 Sandoz Ag Thiazolodiazepines

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US3560515A (en) * 1968-08-05 1971-02-02 Parke Davis & Co New thiazolobenzodiazepine compounds and methods for their production
US3507868A (en) * 1968-10-21 1970-04-21 Sandoz Ag Imidazo(2,1-b)thiazoles and thiazolo(3,2-a)pyrimidines
US3507869A (en) * 1969-02-27 1970-04-21 Sandoz Ag Substituted thiazoles
US3740394A (en) * 1969-07-03 1973-06-19 Seperic Morat Thiazolo and thiazino pyrimidines
US3763142A (en) * 1971-11-09 1973-10-02 Sandoz Ag Thiazolodiazepines

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4489884A (en) * 1980-10-10 1984-12-25 Stedef S.A. Railroad tie cover
US5057513A (en) * 1989-05-25 1991-10-15 Fujisawa Pharmaceutical Co., Ltd. Spiro-thiazepine derivatives useful as paf antagonists

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