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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United States
Prior art keywords
spiro
piperidine
thiazolopyrimidine
hydroxy
hexahydro
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Expired - Lifetime
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US385816A
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English (en)
Inventor
Szarvasi Etienne
Festal Didier
Grand Marcel
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Merck Sante SAS
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LIPHA 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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
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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FR7228747A FR2195426B1 (enrdf_load_stackoverflow) 1972-08-09 1972-08-09

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US (1) US3907800A (enrdf_load_stackoverflow)
JP (1) JPS49132098A (enrdf_load_stackoverflow)
AT (1) AT330173B (enrdf_load_stackoverflow)
AU (1) AU5900173A (enrdf_load_stackoverflow)
BE (1) BE803357A (enrdf_load_stackoverflow)
DD (1) DD109875A5 (enrdf_load_stackoverflow)
DE (1) DE2340122A1 (enrdf_load_stackoverflow)
ES (1) ES417685A1 (enrdf_load_stackoverflow)
FR (1) FR2195426B1 (enrdf_load_stackoverflow)
GB (1) GB1386038A (enrdf_load_stackoverflow)
HU (1) HU165953B (enrdf_load_stackoverflow)
IE (1) IE37986B1 (enrdf_load_stackoverflow)
IL (1) IL42913A0 (enrdf_load_stackoverflow)
NL (1) NL7311048A (enrdf_load_stackoverflow)
SU (1) SU506300A3 (enrdf_load_stackoverflow)
ZA (1) ZA735351B (enrdf_load_stackoverflow)

Cited By (2)

* 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

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4880790A (en) * 1986-01-31 1989-11-14 American Cyanamid Company (Gem-heterocyclodimethanamine-N,N')platinum complexes

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3507869A (en) * 1969-02-27 1970-04-21 Sandoz Ag Substituted thiazoles
US3507868A (en) * 1968-10-21 1970-04-21 Sandoz Ag Imidazo(2,1-b)thiazoles and thiazolo(3,2-a)pyrimidines
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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH498139A (de) * 1967-11-03 1970-10-31 Sandoz Ag Verfahren zur Herstellung neuer 3-Phenyl-6,7-dihydro-5H-thiazolo(3,2-a)pyrimidine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Cited By (2)

* 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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IL42913A0 (en) 1973-11-28
FR2195426B1 (enrdf_load_stackoverflow) 1975-10-17
ZA735351B (en) 1974-07-31
HU165953B (enrdf_load_stackoverflow) 1974-12-28
JPS49132098A (enrdf_load_stackoverflow) 1974-12-18
IE37986L (en) 1974-02-09
SU506300A3 (ru) 1976-03-05
ES417685A1 (es) 1976-06-01
BE803357A (fr) 1973-12-03
DD109875A5 (enrdf_load_stackoverflow) 1974-11-20
ATA699373A (de) 1975-09-15
FR2195426A1 (enrdf_load_stackoverflow) 1974-03-08
DE2340122A1 (de) 1974-02-21
GB1386038A (en) 1975-03-05
AU5900173A (en) 1975-02-13
IE37986B1 (en) 1977-11-23
NL7311048A (enrdf_load_stackoverflow) 1974-02-12
AT330173B (de) 1976-06-25

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