GB2061934A - Mercaptoacyldihydropyrazole carboxylic acid derivatives - Google Patents

Mercaptoacyldihydropyrazole carboxylic acid derivatives Download PDF

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GB2061934A
GB2061934A GB8034001A GB8034001A GB2061934A GB 2061934 A GB2061934 A GB 2061934A GB 8034001 A GB8034001 A GB 8034001A GB 8034001 A GB8034001 A GB 8034001A GB 2061934 A GB2061934 A GB 2061934A
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arylalkyl
acid
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

Novel compounds having the general formula (I): <IMAGE> wherein R1 is hydrogen, alkyl, aryl, arylalkyl or <IMAGE> wherein R6 is alkyl or aryl; R2 is hydrogen, alkyl or haloalkyl; R3 is hydrogen, alkyl, furanyl, thienyl, pyridyl or any of the above-mentioned heterocyclic groups substituted with one or two halogen or alkyl groups; R4 is hydrogen, alkyl or arylalkyl; R5 is hydrogen or alkyl; and n is 0, 1 or 2; and basic salts thereof, have hypotensive activity.

Description

SPECIFICATION Mercaptoacydihydropyrazole carboxylic acid derivatives Compounds having the general formula
and basic salts thereof, have hypotensive activity. In formula I, and throughout the specification, the symbols are as defined below.
R1 is hydrogen, alkyl, aryl, arylalkyl or
wherein R6 is alkyl or aryl; R2 is hydrogen, alkyl or haloalkyl; R3 is hydrogen, alkyl, furanyl (such as 2-furanyl or 3-fumnyl), thienyl, (such as 2-thienyl or 3-thienyl) or pyridyl (such as 2-, 3-or 4-pyridyl) or any of the above-mentioned heterocyclic groups substituted with one or two halogen or alkyl groups; R4 is hydrogen, alkyl or arylalkyl; B5 is hydrogen or alkyl; and n is0, 1 or 2.
The term "aryl", as used herein, either by itself or as a part of a larger group, refers to phenyl or phenyl substituted with one, two or three halogen, alkyl, alkoxy alkanoyl, nitro, amino, alkylamino, dialkylamino, trifluoromethyl, cyano or caboxyl groups. Phenyl is the preferred aryl group.
The term "alkanoyl", as used herein, either by itself or as part of a larger group, refers to groups having 2 to 9 carbon atoms.
The terms "alkyl" and "alkoxy" as used herein, either individually or as part of a larger group, refer to groups having 1 to 8 carbon atoms. Alkyl and alkoxy groups having 1 to 3 carbon atoms are preferred.
The term "halogen", as used herein, either by itself or as part of a larger group, refers to fluorine, chlorine, bromine and iodine. The preferred halogen groups are chlorine and bromine except in the case of "haloalkyl" where fluorine is the preferred "halo" group. Trifluoromethyl is the preferred haloalkyl group.
The compounds of formula I are useful as hypotensive agents. They inhibit the conversion of the decapeptide angiotensin I to angiotensin II and, therefore, are useful in reducing or relieving angiotensin related hypertension. The action of the enzyme renin on angiotensinogen, a pseudoglobulin in blood plasma, produces angiotensin I. Angiotensin I is converted by angiotensin converting enzyme (ACE) to angiotensin II. The latter is an active pressor substance which has been implicated as the causative agent in various forms of hypertension in various mammalian species, e.g., rats and dogs.The compounds of this invention intervene in the angiotensinogen(renin)angiotensin l~(ACE) ) angiotensin II sequence by inhibiting angiotensin converting enzyme and reducing or eliminating the formation of the pressor substance angiotensin II. Thus by the administration of a composition containing one or a combination of compounds of formula I, angiotensin dependent hypertension in the species of mammal suffering therefrom is alleviated. A single dose, or preferably two to four divided daily doses, provided on a basis of about 0.1 to 100 mg. per kilogram of body weight per day, preferably about 1 to 15 mg. per kilogram of body weight per day is appropriate to reduce blood pressure.The substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular, intravenous or intraperitoneal routes can also be employed.
The compounds of this invention can also be formulated in combination with a diuretic for the treatment of hypertension. A combination product comprising a compound of this invention and a diuretic can be administered in an effective amount which comprises a total daily dosage of about 30 to 600 mg., preferably about 30 to 300 mg. of a compound of this invention, and about 15 to 300 mg., preferably about 15 to 200 mg.
of the diuretic, to a mammalian species in need thereof. Exemplary of the diuretics contemplated for use in combination with a compound of this invention are the thiazide diuretics, e.g., chlorthiazide, hydrochlorthiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlothiazide, trichlormethiazide, polythiazide or benzthiazide as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spironolactone and salts of such compounds.
The compounds of formula 1 can be formulated for use in the reduction of blood pressure in compositions such as tablets, capsules or elixirs for oral administration or in sterile solutions of suspensions for parenteral administration. About 10 to 500 mg. of a compound or mixture of compounds of formula I is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
The compounds of this invention can be obtained by reacting an amino acid having the formula
with a small excess of a mercaptoacyl halide having the formula
wherein Rí is alkyl, aryl, arylalkyl, alkyl
and X is chlorine or bromine, to obtain the corresponding products of formula I wherein R1 is other than hydrogen and R4 is hydrogen; i.e., compounds having the formula
The reaction is preferably run in a two phase solvent system such as water/ether or water/ethyl acetate, in the presence of a base such as an alkali metal hydroxide or alkali metal carbonate. While reaction conditions are not critical, more favorable yields will be obtained if the reaction is run within the following parameters.
The ratio of amino acid (formula II) to mercaptoacyl halide (formula III) will preferably be within the range of 1:1.1 to 1:1.5, most preferably within the range of 1:1.1 to 1:1.2. Additional base can be added as needed to maintain the pH of the reaction mixture between about 7.5 and 8.5. Alternatively, instead of the acyl halide (II) a mixed anhydride can be used or a coupling agent can be used.
The compounds of formula I wherein R1 and R4 are both hydrogen can be prepared by deacylation of the corresponding compounds of formula IV wherein Nazis
Hydrolysis of the acylthio group can be accomplished by treatment with aqueous base, ag., ammonium hydroxide or an alkali metal hydroxide.
The compounds of formula I wherein R4 is alkyl or arylalkyl can be obtained by treating the corresponding acid of formula I with the appropriate diazoalkane or with the appropriate alcohol in the presence of a dehydrating agent such as dicyclohexylcarbodiimide and a catalyst such as dimethylaminopyridine.
Alternatively, an acid of formula I can be converted first to an acid halide and then reacted with the appropriate alcohol in the presence of an acid acceptor, e.g., an organic base such as triethylamine.
The compounds of this invention wherein R4 is hydrogen form basic salts with various inorganic and organic bases which are also within the scope of the invention. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts (which are preferred), alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases, e.g., dicyclohexylamine salt, benzathine, N-methyl-Dglucamine, hydrabamine salts, salts with amino acids like arginine, lysine and the like. The non-toxic, physiologically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product.
The amino acids of formula II wherein B3 is hydrogen or alkyl are novel compounds, and as such, they form an integral part of this invention. Those amino acids of formula II wherein B5 is alkyl can be prepared by a two step process. The cyclo-addition of a diazoalkane having the formula (V) R3-CHN2 and an acrylic ester having the formula
yields a 1-pyrazoline derivative having the formula
Tautomerization and hydrolysis of a compound of formula VII to a 2-pyrazoline derivative having the formula
can be accomplished by first treating the 1-pyrazoline derivative with gaseous hydrogen chloride in ether followed by treatment with hydrochloric acid.
Amino acids of formula II wherein B5 is hydrogen can be prepared by reacting a compound having the formula IX CH2=C(CO2alkyl)2 with a diazoalkane of formula Vto obtain a compound having the formula
Treatment of a compound of formula X with gaseous hydrogen chloride in ether, followed by heating the resulting 2-pyrazoline hydrochloride salt to about 60-80"C in hydrochloric acid yields a 2-pyrazoline derivative having the formula
The 4,5-dihydro-3-heterocyclic-1 H-pyrazole-5-carboxylic acids of formula II wherein R3 is a heterocyclic group other than pyridyl, can be prepared using the procedure described in Ann. Pharm. Fr., 36, 67 (1978).As described therein, an acrylic acid derivative can be treated with one equivalent each of hydrazine and potassium hydroxide in aqueous ethanol at reflux for two hours, followed by acidification to obtain a starting compound of formula II. In some cases, anhydrous methanol is superior to aqueous ethanol as the reaction medium. The acrylic acid derivatives required in the preparation can be obtained by reacting glyoxylic acid with the appropriate ketone having the formula
To prepare the 4,5-dihydro-3-heterocyclic-1 H-pyrazole-5-carboxylic acids of formula II wherein B3 is pyridyl, an acetyl pyridine (2-,3-, or 4-, optionally substituted with one or two halogen or alkyl groups) is a-brominated to yield the corresponding bromomethyl pyridyl ketone. An exemplary procedure for the bromination is given in J. Org.Chem., 24, 872 (1959). Reaction of a bromomethyl pyridyl ketone with the appropriate Wittig reagent yields an acrylic acid methyl ester derivative having the formula
An exemplary procedure for the reaction is given in Chem. Ber., 96,465 (1963). Hydrolysis of a methyl ester of formula XIII yields the corresponding acrylic acid derivative which can be reacted with hydrazine and potassium hydroxide in aqueous ethanol (as described above) to yield a 4,5-dehydro-3-heterocyclic-1Hpyrazole-5-carboxylic acid of formula II.
The mercaptoacyl halide derivatives of formula III are prepared by methods known in the art; see, for example, Arkiv. Kimi. Mineral. Geol., 14A (7), 1940; J. Chem. Soc. 2016 (1970) ; J.A.C.S., 69,2328(1947); and J.A.C.S., 69,2334(1947); J. Med. Chem., 7,3 (1964); and J. Chem. Soc., 1371 (1954).
The compounds of formula I each contains at least one asymmetric carbon and accordingly exist in stereoisomeric forms or in racemic mixtures thereof. The above described synthesis can utilize the racemate or one of the enantiomers as starting material. When the racemic starting material is used in the synthetic procedure, the stereoisomers obtained in the product can be separated by conventional fractional crystallization of the diastereomeric salt mixture formed, e.g., with an optically active amine. It is theorized that the activity of the racemic products is due mostly to the S-isomer with respect to the carbon of the amino acid, and this isomer is accordingly preferred.
The following examples are specific embodiments of this invention.
EXAMPLE 1 (#)-3-(2-Furanyl)-4,5-dihydro-1-(3-mercapto-1-oxopropyl)-1H-pyrazole-5-carboxylic acid A) 4F2-Furanyl)-4-oxo-2-butenoic acid A mixture of 14.8g of glyoxylic acid (in 18.5 cc of water) and 22g of 2-acetylfuran is heated at 125-135 C for about 5 hours; the water is removed as it forms via a Dean Stark tube. The mass crystallizes over about a 16 hour period and is dissolved in 600 cc of ethyl acetate and extracted into 600 cc of 10% sodium carbonate.
The aqueous solution is treated with activated charcoal and a filter aid, and then filtered. It is made strongly acid with 20% HCI and the solid which precipitates is extracted with ethyl acetate. The ethyl acetate is dried over MgSO4 and removed to yield a solid residue which is dissolved in 100 cc hot acetonitrile and allowed to cooi for about 16 hours. The solid is filtered to yield 7.29 of the title compound, melting point 153-1 55'C.
B) (I-3-/2-Furanyl-4,5-dihydro- ~H-pyrazole-5-carboxylic acid Potassium hydroxide (660mg) is dissolved in 25 cc of methanol and 1.66g of 4-(2-furanyl)-4-oxo-2-butenoic acid is added. Hydrazine (320 mg) is then added and the solution is refluxed for 2 hours. The methanol is removed and the viscous residue is dissolved in 50 cc of water. The solution is made strongly acid with 20% HCI and a precipitate forms. The solid is filtered quickly to yield 1 .2g of the title compound, melting point 185-190OC, dec.
C) (t)- ?-13-(A cetylthioj- 1-oxopropyl]-3-(2-furanyl)-4,5-dihydro- 1H-pyrazole-5-carboxylic acid (+)-3-(2-Furanyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid (4.5g) is dissolved in 200 cc of water containing 1.38 g of sodium carbonate (pH 9.4) at 10"C. 3-(Acetylthio)propionyl chloride (4.15g) and 20% sodium carbonate solution are added simultaneously maintaining the pH between 8.5 and 9.4 and the temperature at 10 C. The final reaction mixture (pH 9.7) is stirred at room temperature for 2 hours and extracted with ethyl acetate (discarded) and the aqueous layer made strongly acid with 20% HCI. A precipitate forms which is extracted into ethyl acetate immediately. The solvent is dried and removed to yield 4.5 g of crystalline material which cannnot be recrystallized.
D) (#)-3-(2-Furanyl)-4,5-dihydro-1-(3-mercapto-1-oxopropyl)-1H-pyrazole-5-carboxylic acid Aqueous ammonia (12 cc) is stirred under nitrogen at 10 C for 30 minutes, at which point 4.39 of (#)-1-[3-(acetylthio)-1-oxopropyl]-3-(2-furanyl)-4,5-dihydro-1H-pyrazole-pyrazole-5-carboxylic acid is added. The resulting solution is stirred for about 2.5 hours under nitrogen. The solution is extracted with ethyl acetate (discarded) and then made strongly acid with 20% HCI. An oil results which is extracted with 150 cc ethyl acetate. The aqueous layer is extracted with an additional two 150 cc portion of ethyl acetate. The combined organic layers are extracted with 200 cc saturated NaCI and then dried over MgSO4.The solvent is removed to yield 3.79 of semi-crystalline residue which is triturated with ether to yield 2.39 of product melting at 121-123 C. The product did not crystallize readily from any solvent tried.
Analysis calc'd for C11H12n2O4S : N, 10.44; C, 49.24 H,4.51; S,11.95 SH, 100% Found: N,10.14: C,49.39; H,4.59; S,11.43 SH,99% EXAMPLE 2 {+J-4,5-Dihydro- 7-(3-mercapto- I-oxopropyll-3-(2-thienyll- 1H-pyrazole-5-carboxylic acid A) 4-(2- Thienyl)-4-oxocrotonic acid A two phase mixture of 18 grams glyoxyiic acid (an 80% solution of glyoxylic acid in water) and 25.2 grams of 2-acetylthiophene is heated to 125 C with stirring, and heating and stirring are maintained for about 5 hours. A clear solution forms at 115 C and the water formed is removed by means of a Dean-Stark apparatus.
On cooling the residue solidifies. It is dissolved in 100 cc ether and extracted with 150 cc of a 20% solution of Na2CO3. This aqueous solution is treated with activated charcoal, filtered and made strongly acid with 20% HCI. The solid is filtered and dissolved in about 1 L ether. The ether is dried over MgSO4 and removed to yield 19.1g ofthetitle compound, melting point 139-142 C.
B) (#)-4,5-Dihydro-3-(2-thienyl)-1H-pyrazole-5-carboxylic acid Potassium hydroxide (3,3 g) is dissolved in 100 cc of methanol and 9.1 g of 4-(2-thienyl)-4-oxocrotonic acid is added. To the resulting solution is added 29 of hydrazine and the solution is refluxed for 2 hours. The methanol is removed and the viscous residue dissolved in 80 cc of water. The solution is made strongly acid with 20% HCI and a precipitate forms. It is filtered and air-dried to yield 8.19 of the title compound, melting point 163-165 C, dec. After recrystallization from ethanol the compound is constant melting at 171-173 C, dec.
C) (#)-1-[3-(Acetylthio)-1-oxopropyl]-4,5-dihydro-3-(2-thienyl)-1H-pyrazole-5-carboxylic acid (+)-4,5-Dihydro-3-(2-thienyl)-1H-pyrazole-5-carboxylic acid is dissolved in aqeuous Na2CO3 (1.38g) at pH 8.6. The temperature is lowered to 5 C and 3-(acetylthio)propionyl chloride (4.15g) and a 25% solution of Na2CO3 are added simultaneously maintaining the pH at 8-9. The final pH is 8.9 and the reaction is stirred for 2 hours at room temperature. It is then extracted with ethyl acetate and the ethyl acetate is discarded. The aqueous layer is made strongly acid with 20% HCI and the gummy precipitate is extracted with ethyl acetate.
The ethyl acetate is dried over MgSO4 and removed to yield a viscous residue (7.2g) which is triturated with ether to yield 5.1g of material, melting point 127-130 C, dec. After recrystallization from CH3CN (very soluble) the melting point is constant at 134-136 C, dec.
D) {+ J-4,5-Dihydro- i-(3-mercapto- I-oxopropyl)-3-(2-thienyll- 1~-pyrazole-5-carboxylic acid (#)-1-[3-(Acetylthio)-1-oxopropyl]-4,5-dihydro-3-(2-thienyl)-1H-pyrazole-5-carboxylic acid (4.79) is added to a cooled solution of aqueous ammonia (12 cc) and stirred at 10 C under nitrogen for 2 hours. A clear solution forms after about 10 minutes stirring. The aqueous layer is washed with ethyl acetate (discarded) and the aqueous layer made strongly acid with 20% HCI in the presence of ethyl acetate. The aqueous layer is extracted with two add'1 150 cc portions of ethyl acetate and the combined organic layers dried over MgSO4 The solvent is removed yielding 3.29 of product, melting point 138-140 C.
Analysis calc'd for C11 H12N203S2: N, 9.85; C, 46.46; H,4.26; S,22.55; SH 100% Found: N, 9.65; C, 46.79 H,4.34; S,22.35; SH, 99.9% EXAMPLE 3 (#)-3-(2-Thienyl)-4,5-dihydro-1-[D,L-3,3,3-trifluoro-2-(mercaptomethyl)-1-oxopropyl]-1H-pyrazole-5- carboxylic acid A) D,L-[3,3,3-Trifluoro-2-[4-(Methoxy)benzylthio-methyl]]propionic acid A neat mixture of 3.9 g of 2-(trifluoromethyl) acrylic acid [prepared according to the procedures described in J. Med. Chem., 7,3 (1984) and J. Chem. Soc., 1371 (1954)] and 4.3 g of 4-methoxybenzylthiol is stirred at 100-110 C for one hour. The mixture solidifies at room temperature. Recrystallization from cyclohexane affords 6.8 g of the title compound, melting point 72-74 C.
B) (#)-4,5-Dihydro-1-(benzyloxycarbonyl)-3-(2-thienyl)-1H-pyrazole-5-carboxylic acid To a stirred mixture of 9.8 g of (#)-4,5-dihydro-3-(2-thienyl)-1H-pyrazole-5-carboxylic acid (see example 28) and 13.8 g of potassium carbonate in 80 ml of water and 40 ml of acetone there is added slowly 9.3 of benzyl chloroformate dissolved in 50ml of acetone, maintaining the temperature of the mixture at 10-15 Cwith an ice bath. After stirring at room temperature for 2 hours, the mixture is diluted with an equal volume of water and washed twice with ether. The aqueous layer containing some solids, is adjusted to pH 3.0 with 6N HCI and cooled and filtered to obtain the title compound.
C) (#)-4,5-Dihydro-1-(benzyloxycarbonyl)-3-(2-thienyl)-1H-pyrazole-5-carboxylic acid, t-butyl ester A mixture of 6.6 g of (#)-4,5-dihydro-1-(benzyloxycarbonyl)-3-(2-thienyl)-1H-pyrazole-5-carboxylic acid.
5ml of isobutylene, 25 ml of ether and 0.25 ml of concentrated sulfuric acid is shaken in a pressure vessel for about 16 hours. The reaction vessel is vented (-10 C) and the contents are washed with ic3e cold aqueous sodium hydroxide. The organic fraction is dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound.
D) (#)-4,5-Dihydro-3-(2-thienyl)-1H-pyranole-5-carboxylic acid, t-butyl ester A solution of 5.0g of (#)-4,5-dihydro-1-(benzyloxycarbonyl)-3-(2-thienyl)-1H-pyrazole-5-carboxylic acid.
t-butyl ester in 75ml of ethanol containing 0.5 g of 5% palladium on carbon is hydrogenated at atmospheric pressure until the uptake of hydrogen ceases. The catalyst is removed by filtration through Cellte (registered Trade Mark) and the filtrate is concentrated in vacuo to yield the title compound.
E) (#)-3-(2-Thienyl)-4,5-dihydro-1-[3,3,3-trifluoro-2-[4-(methoxy)benzylthiomethyl]-1-oxopropyl]-1H pyrazole-5-carboxylic acid, t-butyl ester A mixture of 2.94 g of D,L-[3,3,3-trifluoro-2[4-(methoxy)benzylthiomethyl]]propionic acid and 2.52 g of (#)-4,5-dihydro-3-(2-thienyl)-1Hpyrazole-5-carboxylic acid, t-butyl ester in 500ml of dichloromethane is stirred at 0 C and treated with 2.06 g of dicyclohexyl carbodiimide. After 30 minutes the cooling bath is removed and stirring is continued at ambient temperature for about 16 hours. Solids are removed by filtration and filtrate is washed with 5% sodium bicarbonate, 5% potassium disulfate and saturated brine and dried over anhydrous magnesium sulfate. Removal of solvent affords the title compound.
F) (#)-3-(2-Thienyl)-4,5-dihydro-1-[D,L-3,3,3-trifluoro-2-(mercaptomethyl)-1-oxopropyl]-1H-pyrazole-5- carboxylic acid A solution of 3.6 g of (#)-3-(2-thienyl)-4,5-dihydro-1-[3,3,3-trifluoro-2-[4-(methoxy)-benzylthiomethyl]-1- oxopropyl-1H-pyrazole-5-carboxylic acid t-butyl ester and 10ml of anisole is cooled to 0 C in an ice bath and 100ml of trifluoroacetic acid is added, followed by 2.3 g of mercuric acetate. The bath is removed and the mixture is stirred at ambient temperature for one hour. After concentration in vacuo, the residue is triturated with ether/pentane and the solid obtained is suspended in water and saturated with hydrogen sulfide gas (10 minutes). The resulting solid in suspension is removed by filtration through Celite. Lyophilization gives the product.
EXAMPLE 4 (#)-3-(2-Pyridyl)-4,5-dihydro-1-(3-mercapto-1-oxopropyl)-1H-pyrazole-5-carboxylic acid A) 4-(2-PYridyl)-4-oxo-2-butenoic acid, methyl ester A solution of 33.4 g of carbomethoxymethylene triphenylphosphine [Helv. Chim Acta. 40, 1242 (1957)] in 500ml of dry benzene under nitrogen is treated with 10 g of 2-(bromoacetyl)pyridine and heated at reflux temperature for 2 hours. The reaction mixture is cooled and filtered to remove carbomethoxymethyl triphenylphosphonium bromide. The filtrate, containing triphenylphosphine, is treated with methyl bromoacetate and heated at reflux temperature for 2 hours. Cooling and filtration removes additional phosphonium salt. The filtrate is concentrated in vacuo yielding the title compound.
B) 4-62-Pyridyl)-4-oxo-2-butenoic acid A mixture of 15 g of 4-(2-pyridyl)-4-oxo-2-butenoic acid, methyl ester in chloroform (50 ml) is stirred with 3.14 g of sodium hydroxide in 50ml of water for 5 hours at room temperature. The aqueous layer is separated, washed with chloroform and acidified with 4.71 g of acetic acid, yielding the title compound.
C) l-l-J-3-(2-Pyridyll-4,5-dihydro- 1H-pyrazole-5-carboxylic acid Potassium hydroxide (3.29 g) is dissolved in 250ml of methanol and 8.85 g of 4-(2-pyridyl)-4-oxo-2 butenoic acid is added. Hydrazine (1.6 g) is then added and the solution is heated at refl ux temperature for 5 hours. Solvent is removed in vacuo and the residue is dissolved in 50 ml of water and treated with 3.0 g of acetic acid yielding the title compound.
D) (#)-1-[3-(Acetylthio)-1-oxopropyl]-3-(2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid (#)-3-(3-Pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid (3.82 g) is dissolved in 100ml of water containing 2.12 g of sodium bicarbonate at 1 00C. 3-(Acetylthio)propionyl chloride (3.9 g) in 15ml of ether and 20% sodium carbonate solution are added simultaneously; the pH is maintained between 7.5 and 8.5. The reaction mixture is then stirred at room temperature for 2 hours and extracted with ether (discarded). The aqueous layer is acidified with acetic acid and extracted with ethyl acetate three times. The solvent is dried over anhydrous magnesium sulfate and concentrated in vacuo, yielding the title compound.
E) (+l-3-(2-Pyridyll-4,5-dihydro- i-(3-mercapto- 1-oxopropylJ- 1H-pyrazole-5-carboxylic acid Aqueous ammonia (12ml of 7N) is stirred at 0-5 C under argon and 3.5 g of (+)-l-[3-(acetylthio)-1- oxopropyl]-3-(2-pyridyl)-4,5-dihydrof-1H-pyrazole-5-carboxylic acid is added. The resulting solution is stirred for 2 hours under argon and is then extracted with ethyl acetate (discarded). The aqueous layer is acidified with acetic acid and extracted with ethyl acetate (three 50ml portions). The combined organic layers are washed with saturated brine, dried over an hydrous magnesium sulfate and concentrated in vacuo to yield the title compound.
EXAMPLES 5-8 Following the procedure of Example 1, parts A, B and C, but substituting the compound of column I for 2-acetylfuran and the acid chloride derivative of column II for3-(acetylthio)propionyl chloride, yields the compound of column III.
Column I Column II Column III 5. 2-acetyl-3-methylthiophene 3-(acetylthio)-2-ethyl- (#)-1-[3-(acetylthio)-2-ethyl proplonyl chloride 1-oxopropyl]-4,5-dihydro-3 (3-methyl-2-thienyl)-1H pyrazole-5-carboxylic acid 6. 2-acetyl-5-chlorothiophene 3-(benzoylthio)-2- (#)-1-[3-(benzoylthio)-2 methylpropionyl methyl-1-oxopropyl]-3-(5 chloride chloro-2-thienyl)-4,5-dihydro 1H-pyrazole-5-carboxylic acid 7. 2-acetyl-5-methylfuran 3,3,3-trifluoro-2- (#)-1-[3,3,3-trifluoro-2-[4 [4-(methoxy)benzyl- (methoxy)benzylthiomethyl] thiomethyl]propionyl 4,5-dihydro-3-(5-methyl-2 chloride furanyl)-1H-pyrazole-5-carboxylic acid ylic acid 8. 2-bromo-3-acetylfuran 3-(acetylthio)-2-methyl- (#)-1-[3-(acetylthio)-2-methyl propionyl chloride 1-oxopropyl]-3-(2-bromo-3 furanyl)-4,5-dihydro-1H pyrazole-5-carboxylic acid EXAMPLES 9-12 Following the procedure of Example 4, but substituting the compound of column I for 2 (bromoacetyl)pyridine and the compound of column II for3-(acetylthio)propionyl chloride, yields the compound of column Ill.
Column I Column II Column III 9. 3-(bromoacetyl)pyridine 3-(acetylthio)-2-methyl- (#)-4,5-dihydro-1-(3-mercapto propionyl chloride 2-methyl-1-oxopropyl)-3-(3 pyridyl)-1H-pyrazole-5-car boxylic acid 10. 4-(bromoacetyl)pyridine 3-(benzylthio)-2-ethyl- (#)-4,5-dihydro-1-(2-ethyl propionyl chloride 3-mercapto-1-oxopropyl)-3 (4-pyridyl)-1H-pyrazole-5 carboxylic acid 11. 2-bromoacetyl-4-methyl (acetylthio)acetyl (#)-4,5-dihydro-1-(2-mercapto pyridine chloride 1-oxoethyl)-3-(4-methyl-2 pyridyl)-1H-pyrazole-5-car boxylic acid 12. 2-bromoacetyl-4-chloro- 4-(acetylthio)butyryl (#)-3-(4-chloro-2-pyridyl) pyridine chloride 4,5-dihydro-1-(4-mercapto 1-oxobutyl)-1H-pyrazole-5 carboxylic acid EXAMPLE 13 li(S), 657-4, 5-Dih ydro- 1-[3-(acetylthioJ-2-methyl- 1-oxopropyll- ill-p yrazole-5-carb oxylic acid A) Diethyl-3,4dihydro-5H-pyrazole-5,5-dicarboxylic acid A solution of 29.3 g of diethyl ethylene-malonate in 300 ml of ether is treated with ethereal diazomethane until a slight yellow color persists. Excess diazomethane is removed on a steam bath, and the solution is then concentrated in vacuo to give 32.5 g of the title compound as an oil.
Analysis calc'd for C9H14N204: C, 50.45; H, 6.58 N, 13.08 Found: C, 50.34, H, 6.61; N, 12.90 B) Diethyl-4,5-dihydro- 1H-pyrazole-5,5-dicarboxylic acid, hydrochloride salt A cold solution of 32.5 g of diethyl-3,4-dihydro-5H-pyrazole-5,5-dicarboxylic acid in 250 ml of ether is treated with a slight excess of gaseous hydrogen chloride. The product appears as an oil, and slowly crystallizes on standing at room temperature for several hours to give 31.2 g of the title hydrochloride salt, melting point 90-94 C.
Analysis calc'd for C9H14N2O4.HCl : C, 43.12; H, 6.03 N, 11.17 Found: C,43.17; H,6.08; N,11.21 C) 4,5-Dihydro- IH-pyrazole-5-carboxylic acid A solution of 18.5 g of diethyl-4,5-dihydro-1H-pyrazole-5,5-dicarboxylic acid, hydrochloride salt in 72 ml of 1.07N hydrochloric acid is stirred and heated at 70-75 C (oil bath) until evolution of carbon dioxide ceases (6 hours). The solution is cooled, and the water evaporated in vacuo to give 12.0 g of a viscous residue.
To remove the HCI from the above crude product, an aqueous solution is slowly passed through a column of 100 ml of 20-50 mesh Dowex 50W-X8 resin (H+). The strongly acidic initial fractions are set aside for later purification over regenerated resin. The neutral column is treated with 3N NH40H. Evaporation of the eluate gives 4.8 g of impure amino acid. An additional 1.5 g of similar material is obtained from the acidic fractions described above (the initial acidic fractions can be significantly reduced in volume by an extended batch slurry of a portion of the resin with the aqueous hydrochloride before placing the resin in the column).
A solution of this material in a small amount of methanol is placed on seven preparative plates (Merck2 mm) and developed in methanol (6 hours). Of the three UV absorbing areas detected, the center portion contains the desired product, which is obtained by methanol extraction to give 3.45 g of the title compound as an oil.
The words "Dowex" and "Merck" are registered Trade Marks.
D) [1(S), 557-4, 5-Dih ydro- 1-[3-8acetylthio)-2-methyl- 1-oxopropyl]-1H-pyrazole-5-carboxylic acid The above amino acid is combined with 1.55 g of similarly derived product and dissolved in 40 ml of water.
The pH is raised to 8.0 using 1 N NaOH. An equal volume of ethyl acetate is added and the mixture is stirred during the drop-wise addition of a solution of 9.0 g of D-3-(acetylthio)-2- methylpropionyl chloride in 20 ml of ethyl acetate. The pH is maintained between 7.5-8.0 with 6N NaOH during the one hour procedure. After completion of addition, the pH continues to fall and is kept at the optimum range with the continual addition of base. After 6 hours, the reaction is terminated by separating the ethyl acetate and treating the aqueous portion with 3N HCI to pH 2.0. Extraction of the resulting oil with ethyl acetate gives 6.6 g of impure product.
Additional product is obtained by combining the original ethyl acetate layer with the extracted aqueous solution and treating this with 6N NaOH to pH 8.0. An additional 2.0 g of acid chloride is gradually added and the reaction pH is maintained at 7.5-8.0 for 7 hours with the necessary addition of base. The work-up procedure yields 3.1 g of material having the same Rf values as the first fraction.
The above procedure is repeated for a third time (6 hours) without the addition of acid chloride. The yield of impure product is 1.6 g. The three portions are combined.
A small amount of this material is dissolved in ethyl acetate and treated with an equivalent amount of 1-adamantanamine. Conversion of the resulting salt backto the acid gives a homogeneous product.
On the basis of this result,11.1 g of the impure acylated amino acid is dissolved in 150 ml of ethyl acetate and treated with 6.5 g of 1-adamantanamine. The amine salt immediately precipitates to give 13.1 g of colorless material, melting point 167-169 C [Ct]DO = -42" (MeOH). TLC analysis of a small amount of this material that is converted to the free acid shows that no purification has taken place, and the adamantanamine salt formation can be eliminated from future work. The amine salt (13.1 g) is then dissolved in 25 ml of 3N HCI and extracted twice with CHCl3. The extracts are combined, dried, and evaporated to give 10.7 g of a wax-like semi-solid mixture. A solution of this material in 15 ml of methanol is distributed equally on ten 7" x 7" 2 mm silica gel plates (Uniplate) and developed in methanol/ethyl acetate (1:1). Of the two UV absorbing portions, the faster moving portion contained 5.7 g of impurity and the slower moving portion contained 3.8 g of a cream colored solid, melting point 170-175"C. Both products are obtained by methanol extraction.
Elemental analysis of the above solid shows it to be the adamantanamine salt of the acid. A solution of this material in 9 ml of 3N HCI at room temperature gradually forms 0.84 g of a colorless solid, melting point 100-102 C [o] = - 180' (MeOH). This material is treated with 6 ml of hot methylene chloride, diluted with 15 ml of ether and kept at 5 C for one hour. After filtration to remove silica gel, the filtrate is diluted with with 15 ml of ether and cooled at 5 C for 3 hours to give 0.04 g of solid, melting point 240-245 C.The filtrate from the above purification is evaporated in vacuo to yield 0.70 g of a colorless solid, melting point 100-102 ; [&alpha;]D20 = -183 (MeOH). Crystallization from 4.5 ml of hot water yields 0.56 g of desired product, melting point 104-106 , [&alpha;D= -205 (MeOH).
Analysis calc'd for C10H14N2O4S-H2O : C, 43.46; H, 5.83; N, 10.14 Found: C, 43.91: H, 5.74; N, 9.96 EXAMPLE 14 [1-(S),5S]-4,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrazole-5-carboxylic acid A solution of 0.56 g of [1(S),5S]-4,5-dihydro-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-1H-pyrazole-5carboxylic acid in 5 ml of cold 6N ammonium hydroxide is stirred in an argon atmosphere for 1 hour at room temperature. The solution is extracted with ethyl acetate and treated with 3N hydrochloric acid to pH 2. The product is extracted twice with ethyl acetate, dried and evaporated to an oil which slowly solidifies during storage at 5 C. This material is dried in vacuo at 85 C for several hours to remove a moderate amunt of NH4CI. The yield of product is 0.28 g, melting point 108-110 C, [a]2D0 = - 1710.
Analysis calc'd for C8H12N203S; C,44.42; H, 5.59; N, 12.95; S, 14.82 Found: C,44.15; H, 5.71; N, 12.88; S, 14.56 EXAMPLES 15-17 Following the procedure of Example 13, but substituting the compound listed in column I for diazomethane and the compound listed in column II for D-3-(acetylthio)-2-methylpropionyl chloride, yields the compound listed in column III.
15 diazoethane D-3-(acetylthio)-2-(trifluoro- [1(S),5S]-4,5-dihydro-1-[3-(acetyl methyl)propiuonyl chloride thio)-2-(trifluoromethyl)-1-oxo propyl]-3-methyl-1H-prazoie-5 carboxylic acid 16 1-diazopropane D-3-(acetylthio)propionyl [1(S),5S]-4,5-dihydro-1-[3-(acetyl chloride thio)-1-oxopropyl]-3-ethyl-1H prazole-5-carboxylic acid 17 1-diazobutane D-3-(benzoylthio)-2-methylpro- [1(S),5S]-4,5-dihydro-1-[3-(benzoyl pionyl chloride thio)-2-methyl-1-oxopropyl]-3 (n-propyl)-1H-prazole-5-carboxylic acid EXAMPLE 18 [1(S),5S]-4,5-Dihydro- 1-[3-tacetylthio)-2-methyl- 1-oxoprop ylJ-5-meth vi- 1H-pyrazole-5-carboxylic acid A) Methyl-3,4-dEhydro-5-methyl-5H-pyrazole-5-carboxylic acid A solution of 10 g of methyl methacrylate in 100 ml of ether is treated with an excess of ethereal diazomethane for about 16 hours. The ether is removed in vacuo to give 12.5 g of the title compound as an oil. Examination of the oil on thin layer chromatography silica gel plates using 40% ethyl acetate/hexane shows a single spot at Rf=0.34, visualized with phosphomolybdic acid plus heat. The oil has the following spectral characteristics: NM R(13C,CDC13ppm), 170.9(C-1), 94.1(C-2), 28.0(C-3), 77.1(C-4), 21.1(C-5), 52.3(C-6), IR(neat), 5.78u(CO2CH3), 6.5u(N=N).
B) Methyl-4,5-dEhydro-5-methyl- 1H-pyrazole-5-carboxylic acid A solution of 0.5 g of methyl-3,4-dihydro-5-methyl-5H-pyrazole-5-carboxylic acid in 10 mi of ether is treated with gaseous hydrogen chloride, rapidly forming an amorphous precipitate. After cooling tor about 16 hours at 5 C, ether is decanted and the residue is washed several times with ether. The residue is dissolved in water, made basic with saturated sodium bicarbonate and extracted with ether. The ether extracts are washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 60 mg of product as an oil.
The original ether washes are washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous magneisum sulfate and concentrated to give 260 mg of product identical to the 60 mg obtained above. Examnation of the combined product on thin layer chromatography silica gel plates using 40% ethyl acetate/hexane shows a singel spot at Rf =0.34, visualized with phosphomolybdic acid plus heat. The product has the following spectral characteristics: NMR (13C, CDCl3, ppm), 175.2(C-1), 66.4(C-2), 43.6(C-3), 142.7(C-4),23.5(C-5), 52.3(C-6).
C) 4,5-Dihydro-5-methyl- illp yrazole-5-carboxylic acid A solution of methyl-4,5-dihydro-5-methyl-1H-pyrazole-5-carboxylic acid in chloroform is stirred with 1 N sodium hydroxide at room temperature for 5 hours. The aqueous layer is separated, acidified with 1.5 equivalents of hydrochloric acid and placed on a column of AG50W-X8 (H+ form) ion exchange resin. The column is washed with water until neutral and the product is then eluted with 3N ammonium hydroxide.
Evaporation in vacuo yields the title compound.
D) [1(S),5S]-4,5-Dihydro- ; i-[3-(acetylthio)-2-meth vi- 1-oxopropyll-5-methyl- 1H-pyrazole-5-carboxylic acid- Following the procedure of Example 1 D, but substituting 4,5-dihydro-5-methyl-1H-pyrazole-5-carboxylic acid for 4,5-dihydro-1H-pyrazole-5-carboxylic, acid, yields the title compound.

Claims (62)

1. A compound of the following general formula (I):
wherein R1 represents hydrogen, alkyl, aryl, arylalkyl or
wherein B6 is alkyl or aryl; B2 represents hydrogen, alkyl or haloalkyl; B3 represents hydrogen, alkyl, furanyl, thienyl or pyridyl or such a heterocyclic groups substituted with one or two halogen or alkyl groups; R4 represents hydrogen, alkyl or arylalkyl; B5 represents hydrogen or alkyl; and n is 0, 1 or 2; the terms alkyl, aryl, arylalkyl, haloalkyl and halogen being each as hereinbefore defined.
2. A compound as claimed in Claim 1, containing an aryl andlor arylalkyl group in which the aryl moiety is phenyl.
3. A compound as claimed in Claim 1 or 2, containing an alkyl and/or arylalkyl group in which the alkyl moiety has from 1 to 3 carbon atoms.
4. A compound as claimed in any one of Claims 1 to 3, wherein B3 represents furanyl, thienyl or pyridyl or such a heterocyclic group substituted with one or two halogen or alkyl groups.
5. A compound as claimed in Claim 4, in which B3 represents a said heterocyclic group substituted with chlorine or bromine.
6. A compound as claimed in any one of Claims 1 to 5, in which B2 represents a haloalkyl in which the halogen is fluorine.
7. A compound as claimed in Claim 6, in which the haloalkyl is trifluoromethyl.
8. A compound as claimed in any one of Claims 1 to 5, wherein R2 represents methyl.
9. A compound as claimed in any one of Claims 1 to 8, wherein R1 represents hydrogen.
10. A compound as Claimed in any one of Claims 1 to 8, wherein R1 represents
11. A compound as claimed in any one of Claims 1 to 10, wherein R4 represents hydrogen.
12. A compound as claimed in any one of Claims 1 to 1 1,wherein n is 1.
13. A compound as claimed in any one of Claims 1 to 5, wherein B5 represents hydrogen.
14. A compound as claimed in Claim 13, wherein B2 represents hydrogen, methyl or trifluoromethyl.
15. A compound as claimed in Claim 13, wherein n is 1.
16. A compound as claimed in Claim 13, wherein B3 represents 2furanyl or 2-thienyl.
17. Any one of the compounds claimed in Claim 1, and identified in the foregoing individual examples 1 to 18.
18. (1 (S),5S)-4,5-dihydro-1 -(3-(acetylthio)-2-methyl-1 -oxopropyl)-1 ll-pyrazole-5-carboxyl ic acid.
19. (1 (S),5S)-4,5-dihydro-1 -(3-mercapto-2-methyl-1 -oxopropyl)-1H-pyrazole-5-carboxylic acid.
20. (+) -3-(2-fu ranyl )-4,5-dihydro-1 -(3-mercapto-1 -oxopropyl)-1 H-pyrazole-5-carboxylic acid.
21. (+) -4,5-dihydro-1 -(3-merca pto-1 -oxopropyl)-3-(2-th ienyl-1 -H-pyrazole-5-ca rboxylic acid.
22. A racemic mixture of stereoisomers of a compound claimed in Claim 1.
23. A separate stereoisomer of a compound as claimed in Claim 1.
24. An S-isomer with respect to the carbon of the amino acid of a compound as claimed in Claim 1.
25. A basic salt of a compound as claimed in any one of the preceding Claims.
26. A method of preparing a compound of the general formula(la):
wherein R2, R3, R5 are as defined in Claim 1, R4 represents hydrogen and R1 represents alkyl, aryl, arylalkyl or
wherein B6 is alkyl or arylalkyl; alkyl, aryl, arylalkyl, haloalkyl and halogen being as hereinbefore defined, which method comprises reacting an amino acid of the general formula (II) :
wherein B3 and Rg are as hereinbefore defined, with a small excess of a mercaptoacyl halide of the general formula (III):
wherein R2 is as hereinabove defined, X represents chlorine or bromine and R; represents alkyl, aryl, arylalkyl, alkyl
alkyl, aryl, arylalkyl, alkyl -C- and
being as herein before defined.
27. A method as claimed in Claim 26, wherein the reaction is effected in a two phase solvent system in the presence of a base.
28. A method as claimed in Claim 27 wherein the two phase solvent system is water/ether or water/ethyl acetate.
29. A method as claimed in Claim 26 or 27 wherein the base is alkali metal hydroxide or alkali metal carbonate.
30. A method as claimed in any of Claims 26 to 29 wherein the ratio of amino acid to mercaptoacyl halide isfrom 1:1.1 to 1:1.5.
31. A method as claimed in Claim 30 wherein the ratio of amino acid to mercaptoacyl halide is from 1:1.1 to 1:1.2.
32. A method as claimed in any of Claims 26 to 31 wherein the pH of the reaction mixture is maintained at from 7.5 to 8.5.
33. A method of preparing a compound of the general formula (la):
wherein R2, R3, R5 are as defined in Claim 1, R4 represents hydrogen and R1 represents alkyl, aryl, arylalkyl or
wherein B6 is alkyl or arylalkyl; alkyl aryl, arylalkyl, haloalkyl and halogen being as hereinbefore defined, which method comprises reacting an amino acid of the general formula (ill):
wherein B3 and B5 are as hereinbefore defined, with a suitable mixed anhydride or a suitable coupling agent.
34. A method of preparing a compound of the general formula (Ib):
wherein R1 and R4 both represent hydrogen and R2, B3 and B5 are as defined in Claim 1 and the terms alkyl, aryl, arylalkyl, haloalkyl and halogen are as hereinbefore defined, which method comprise deacylation of a compound of the general formula (Ic):
wherein R4 represents hydrogen, R2, B3 and B5 are as defined in Claim 1, R1 represents alkyl
and alkyl, aryl, arylalkyl, haloalkyl and halogen are as hereinbefore defined.
35. A method as claimed in Claim 34, wherein the compound of general formula Ic is prepared by the method of any one of Claims 26 to 33 wherein in the compound of the formula III, R; represents alkyl
36. A method as claimed in Claim 34 or 35, wherein deacylation is accomplished by treatment with an aqueous base such as ammonium hydroxide or an alkali metal hydroxide.
37. A method of preparing a compound of the general formula (Id):
wherein R1, R2, R3 and R5 are as defined in Claim 1 and R4 is alkyl or arylalkyl ; alkyl, aryl, arylalkyl, halcalkyl and halogen being as hereinbefore defined, comprising treating the corresponding acid with the appropriate diazoalkane or alcohol in the presence of a dehydrating agent and a catalyst.
38. A method as claimed in Claim 37, wherein the dehydrating agent is dicylocarbodiimide.
39. A method as claimed in Claim 37 or 38, wherein the catalyst is dimethylaminopyridine.
40. A method of preparing a compound of the general formula (Id):
wherein R1, R2, B3 and B5 are as defined in Claim 1, R4 represents alkyl or arylalkyl; alkyl, aryl, arylalkyl, haloalkyl and halogen being as hereinbefore defined, which method comprises preparing the corresponding acid, converting to an acid halide and then reacting with the appropriate alcohol in the presence of an acid acceptor.
41. A method as claimed in Claim 36, wherein the acid acceptor is trimethylamine.
42. A method of preparing a compound as claimed in Claim 1, substantially as hereinbefore described with respect to any one of the individual Examples 1 to 18.
43. A compound as claimed in Claim 1, prepared by a method as claimed in any one of Claims 26 to 42.
44. A pharmaceutical composition comprising at least one compound as claimed in any one of Claims 1 to 25 and 43 or a non-toxic physiologically acceptable basic salt thereof, together with a pharmaceutically acceptable carrier, excipient and/or diluent therefor.
45. A compound as claimed in any one of Claims 1 to 25 and 43, or a composition as claimed in Claim 44 for use as a hypotensive agent.
46. A formulation comprising a compound as claimed in any one of Claims 1 to 25 and 43 and a diuretic.
47. A compound of the general formula (ill):
wherein B3 represents hydrogen or alkyl and B5 represents hydrogen or alkyl.
48. A compound as claimed in Claim 47, containing an alkyl group having from 1 to 8 carbon atoms.
49. A compound as claimed in Claim 48, wherein the alkyl group has from 1 to 3 carbon atoms.
50. A compound as claimed in any one of Claims 47 to 49 wherein B3 represents hydrogen.
51. A compound as claimed in any one of Claims 47 to 49 wherein B5 represents hydrogen.
52. A compound as claimed in any one of Claims 47 to 49, wherein B3 represents alkyl.
53. A compound as claimed in any one of Claims 47 to 49, wherein B5 represent alkyl.
54. 4,5-dihydro-1H-pyrazole-5-carboxylic acid.
55. A method of preparing a compound of the general formula (lla):
wherein B3 is hydrogen or alkyl and B5 is alkyl, which method comprises tautomerising and hydrolysing a compound of the general formula (VII):
wherein R4 is as defined in Claim 1.
56. A method as claimed in Claim 55, wherein the tautomerisation and hydrolysis are carried out by treatment with gaseous hydrogen chloride in ether followed by treatment with hydrochloric acid.
57. A method as claimed in Claim 55 or 56 wherein the compound of the general formula (VII)
is prepared by cycloaddition of a diazoalkane of the general formula (V): (V) B3-CHN2 and an acrylic ester of the general formula (VI):
58. A method of preparing a compound of the general formula (llb):
wherein B3 represents hydrogen or alkyl and B5 is hydrogen, comprising the step of treating a compound of the general formula (X):
with gaseous hydrogen chloride in ether, followed by heating the resulting 2-pyrazoline hydrochloride salt to from 60"C to 80"C in hydrochloric acid.
59. A method as claimed in Claim 58, wherein the compound of the general formula (X) is prepared by reacting a compound of the general formula (IX): (IX) CH2=C(CO2alkyl)2 with a diazoalkane of the general formula (V): (V) B3-CHN2
60. A method of preparing a compound as claimed in Claim 47, substantially as hereinbefore described with reference to any one ofthe Examples 13 and 15 to 18.
61. A compound as claimed in Claim 47, when prepared by a method as claimed in any one of Claims 55 to59.
62. The features hereinbefore disclosed, or their equivalents, in any novel selection.
GB8034001A 1979-10-25 1980-10-22 Mercaptoacyldihydropyrazole carboxylic acid derivatives Expired GB2061934B (en)

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GB08300874A Expired GB2129420B (en) 1979-10-25 1983-01-13 Pyrazoline carboxylic acids

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CA (1) CA1156236A (en)
DE (1) DE3040258A1 (en)
FR (2) FR2482099A1 (en)
GB (2) GB2061934B (en)
IT (1) IT1134037B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2139216A (en) * 1983-01-24 1984-11-07 Roussel Uclaf Heterocyclic medicaments
GB2162519A (en) * 1984-07-20 1986-02-05 Roussel Uclaf New 4-oxo-2-butenoic acid derivatives

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3013015A (en) * 1959-09-29 1961-12-12 Gen Aniline & Film Corp 1-substituted-2-pyrazoline-3-carbox-aldehyde dye intermediates
US3666772A (en) * 1970-02-26 1972-05-30 Carlisle Chemical Works Preparation of pyrazolines by cyclization of an azine
US4105776A (en) * 1976-06-21 1978-08-08 E. R. Squibb & Sons, Inc. Proline derivatives and related compounds
US4211786A (en) * 1979-03-08 1980-07-08 E. R. Squibb & Sons, Inc. Mercaptoacyldihydropyrazole carboxylic acid derivatives
US4288368A (en) * 1979-07-30 1981-09-08 E. R. Squibb & Sons, Inc. Dithioacylproline derivatives

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2139216A (en) * 1983-01-24 1984-11-07 Roussel Uclaf Heterocyclic medicaments
US4814348A (en) * 1983-01-24 1989-03-21 Roussel Uclaf Therapeutic compositions containing derivatives of acrylic acid having an oxygen-containing heterocycle, therapeutic treatment therewith and new compounds
GB2162519A (en) * 1984-07-20 1986-02-05 Roussel Uclaf New 4-oxo-2-butenoic acid derivatives

Also Published As

Publication number Publication date
GB2129420A (en) 1984-05-16
FR2482099B1 (en) 1983-09-30
GB8300874D0 (en) 1983-02-16
DE3040258A1 (en) 1981-05-21
GB2061934B (en) 1984-06-06
FR2474494B1 (en) 1983-06-17
IT1134037B (en) 1986-07-24
IT8025575A0 (en) 1980-10-24
FR2482099A1 (en) 1981-11-13
GB2129420B (en) 1984-10-31
FR2474494A1 (en) 1981-07-31
CA1156236A (en) 1983-11-01

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