CA1156236A - Mercaptoacyldihydropyrazole carboxylic acid derivatives - Google Patents

Mercaptoacyldihydropyrazole carboxylic acid derivatives

Info

Publication number
CA1156236A
CA1156236A CA000361332A CA361332A CA1156236A CA 1156236 A CA1156236 A CA 1156236A CA 000361332 A CA000361332 A CA 000361332A CA 361332 A CA361332 A CA 361332A CA 1156236 A CA1156236 A CA 1156236A
Authority
CA
Canada
Prior art keywords
hydrogen
carboxylic acid
dihydro
pyrazole
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
CA000361332A
Other languages
French (fr)
Inventor
George C. Rovnyak
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ER Squibb and Sons LLC
Original Assignee
ER Squibb and Sons LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US06/088,425 external-priority patent/US4254267A/en
Priority claimed from US06/140,355 external-priority patent/US4266065A/en
Application filed by ER Squibb and Sons LLC filed Critical ER Squibb and Sons LLC
Application granted granted Critical
Publication of CA1156236A publication Critical patent/CA1156236A/en
Expired legal-status Critical Current

Links

Classifications

    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

ABSTRACT
Compounds having the formula and basic salts thereof, have hypotensive activity.
In formula I, and throughout the specification, the symbols are as defined below.
Rl is hydrogen, alkyl, aryl, arylalkyl or R6-?- wherein R6 is alkyl or aryl; R2 is hydrogen, alkyl or haloalkyl; R3 is hydrogen, alkyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 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; R5 is hydrogen or alkyl; and n is 0, 1 or 2.

Description

MERCAPTOACYLDIHYDROPYRAZOLE CARBOXYLIC ACID
DERIVATIVES
Compounds having theRformula 1 ( 2)n and basic salts thereof, have hypotensive activity.
In formula I, and throughout the specification, the symbols are as defined below.
~ Rl is hydrogen, alkyl, aryl, arylalkyl or R6-~- wherein R6 is alkyl or aryl; R2 is hydrogen, alkyl or haloalkyl; R3 is hydrogen, alkyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-, 3- or 4-pyridyl lS 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.
The term "aryl", as used throughout the specification, either by itself or as part of a larser group, refers to phenyl or phenyl substituted with one, two or three halogen, alkyl, alkoxy, alkanoyl, nitro, amino, alkylamino, dialkylamino, trifluoromethyl, cyano or carboxyl groups. Phenyl is the preferred aryl group.
The term "alkanoyl", as used throughout the specification, either by itself or as part of a larger group, refers to groups having 2 to ~ carbon atoms.

The terms "alkyl" and "alkoxy" as used throughout the specification, either individually or as part of a larger group, refer to groups having 1 to 8 carbon atoms. Alkyl and alkoxy S groups having 1 to 3 carbon atoms are preferred.
The term "halogen", as used throughout the specification, 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 ~r 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 I~(ACE)~
angiotensin II sequence by inhibiting angiotensin converting enzyme and reducing or eliminating the forn~tion of the pressor substance angiotensin II. Thus by the administration of a composition containinq one or a combination of compounds of formula I, angiotensin dependent hypertension in the s~ecies of mammal sufferiny therefrom is alleviated. A single dose, or preferably two S 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 lS 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 comhination with a compound of this invention are the thiazide diuretics, e.g., chlorthiazide, hydrochlorthiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methychlothiazide, trichlor-methiazide, polythiazide or benzthiazide as well as ethacrynic acid, ticrynafen, chlorthalidone, 1 156236 ~ 2l9/l99 ~, furosemide, musolimine, bumetanide, triamterene, amiloride and spironolactone and salts of such compounds.
The compounds of formula I 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 lS amound 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 II ~

HN I C-OH

with a small excess of a mercaptoacyl halide having the formula 1-S-(CEI2)n-cH-c-x ~ O

tl~21'~/199 o wherein Rl is alkyl, aryl, arylalkyl, alkyl-C-o or aryl-C- and X is chlorine or bromine, to obtain the correspondin~ products of formula I wherein Rl is other than hydro~en and ~4 is hydrogen;
i.e., compound 5 havi nq the formula , R2 ¦ ¦
~l-S~(C~2)n CH C N ~ C-OH
R5 o 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 followin~ parameters. The ratio of amino acid (formula II) to mercaptoacyl halide (formula III) will preferably be within the range ofl:l.l to 1:1.5, most preferably within the range ofl:l.l 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 tlle acyl halide (II) a mixed anhydride can be used or a coupling agent can be used.
The compounds of formula I wherein Rl and R4 are both hydrogen can be prepared by deacylation of the corresponding compounds of formula I~' wherein Rl is alkyl-~- or aryl-~-.

1 156236 ~IA219/199 Hydrolysis of the acylthio group can be accomplished by treatment with aqueous base, e.~., am~onium 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 ~resence 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.q., dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, 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 usef~1, e.g., in isolating or purifying the product.
The amino acids of formula II wherein ~ is hydrogen or alkyl are novel compounds, and as such, they form an integral par~ o~ ~his invention. Those amino acids of formula II wherein R5 i5 alkyl can be 1158236 ~ 2l9/lg9 prepared bv a two steP Process. The cyclo-~ddition of a diazoalkane having the formula and an acrylic ester having the formula VI IClH2 alkyl-C-C-OR4, - yields a l-pyrazoline derivative having the formula ~
N O
N -C-OR4.

Tautomerization and hydrolysis of a compound of formula VII to a 2-pyrazoline derivative having the formula : N ~
X~ ¦ C-OH
alkyl can be accomplished by first treating the l-pyrazoline derivative with gaseous hydrogen chloride in ether followed by treatment with hydrochloric acld.
Amino acids of formula II wherein R5 is hydroyen can be prepared by reacting a compound having the formula IX
cH2=c(co2alkyl)2 with a diazoalkane of formula V to obtain a compound having the formula X N
I C02alkyl C02alkyl .
Treatment of a compound of formula X with gaseous hydrogen chloride in ether, followed by heating the resulting 2-pyrazoline hydrochloride salt to about 60-80C in hydrochloric acid yields a 2-pyrazoline derivative having the formula XI I ~

The 4,5-dihydro-3-heterocyclic-lH-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 ~ormula ; XII

:' .~

To prepare the 4,5-dihydro-3-heterocyclic-lH-pyrazole-5-carboxylic acids of formula II
wherein R3 is pyridyl, an acetyl pyridine (2-,3-, or 4-, optionally substituted with one or two halogen or alkyl groups) is ~-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 XIII

R3-1CI-CH=CH ~l OCH3 An exemplary procedure for the reaction is given in Chem. Ber., 96, 465 (1963). Hydrolysis of a methyl ester of formulaXIII 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-lH-pyrazole-5-carboxylic acid of formula II.
The mercaptoacyl halide derivatives of formula III are ~repared 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 (lg54).

l 1~6236 HA219/199 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 S 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 conven-tional fractional crystallization of the diastereo-10 meric salt mixture formed, e g., with an opticallyactive 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.

,::

. 1156236 1~21~/'99 Example 1 (+)-3-(2-Furanyl)-4,5-dihydro-1-(3-mercapto-1-oxopropyl)-lH-pyrazole-5-carboxylic acid _ A) 4-(2-Furanyl)-4-oxo-2-butenoic acid A mixture of 14.8g of glyoxylic acid (in 13.5 cc of water) and 22g of 2-acetylfuran is heated at 125-135C for about 5 hours; the water is removed as it forms via a Dean Stark tube. The mass ~
cyrstallizes 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~ HCl and the solid which precipitates is extracted with ethyl acetate. The ethyl acetate is dried over MgSO4 and removed ~o yield a solid residue which is dissolved in 100 cc hot acetonitrile and allowed to cool for about 1~6 hours. The solid is filtered to yield 7.2g of the title compound, melting point 153-155C.

B) (+)-3-(2-Furanyl)-4,5-dihydro-lH-pyrazole-5-carboxylic acid Potassium hydroxide (660mg~ is dissolved in 25 cc of methanol and 1.66g of 4-(2-uranyl)-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 1156236 ~ 9/l99 is made strongly acid with 20% HCl and a precipitate forms. The solid is filtered quickly to yield 1.2g of the title compound, melting point 185-190C, dec.

C) (~ [3-(Acetylthio)-l-oxopropyl]-3-(2-furanyl)-4,5-dihydro-lH-pyrazole-5-carboxylic acid (+)-3-(2-Furanyl)-4,5-dihydro-lH-pyrazole-5-carboxylic acid (4.5g) is dissolved in 200 cc of water containing 1.38g of sodium carbonate(pH 9.4) at 10C. 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 10C. 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% HCl. A precipitate forms which i5 extracted into ethyl acetate immediately.
~he solvent is dried and removed to yield 4.5 g of crystalline material which cannot be recrys-talliæed.
. ~
D) (+)-3-(2-Furanyl)-4,5-dihydro-1-(3-mercapto-1-oxopropyl)~ pyrazole-5-carboxylic acid Aqueous ammonia (i2 cc) is stirred under nitrogen at 10C for 30 minutes, at which point 4.3g of (i)-1-[3-(acetylthio)-1-oxopropyl]-3-~; (2-furanyl)-4,5-dihydro-lH-pyrazole-5-carboxylic ~- 30 acid is added. The resulting solution is stirred for about 2.5 hours under nitrogen. The solution ~IA 219/199 is extracted with ethyl acetate (discarded) and then made strongly acid with 20~ HCl. An oil results which is extracted with 150 cc ethyl acetate. The aqueous layer is extracted with an additional two 150 cc portions of ethyl acetate.
The combined organic layers are extracted with 200 cc saturated NaCl and then dried over MgSO4.
The solvent is removed to yield 3.7g of semi-crystalline residue which is triturated with ether to yield 2.3g of product melting at 121-123C.
The product does not crystallize readily from any solvent tried.
Analysis calc'd for CllH12N2O4S:N, 10.44; C, 49-24 ~, 4.51; S, 11.95 SH, 100%
Found:N, 10.14; C, 49.39;
H, 4.59; S, 11.43 SH, 99%

~ Example 2 ~ (+)-4,5-Dihydro-1-(3-mercapto-1-oxopropyl)-3-; (2-thienyl)-lH-pyrazole-5-carboxylic acid A) 4-(2-Thienyl)-4-oxocrotonic acid A two phase mixture of 18 grams glyoxylic acid (an 80% solution of glyoxylic acidin water) and 25.2 grams of 2-acetylthiophene is heated to 125C with stirringtand heating and stirring are ; maintained for about 5 hours. A clear solution -~ 30 forms at 115C and the water formed is removed - by means of a Dean-Stark apparatus. On cooling ~ the residue solidifies. It is dissolved in 100 cc 1156236 11~219~199 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% HCl. The solid is filtered and dissolved in about 1 L ether. The ether is dried over MgS04 and removed to yield l9.1g of the title compound, melting point 139-142C.

B) ~i)-4~5-Dihydro-3-(2-thienyl)-lH-pyrazole-5-carboxylic acid Potassium hydroxide (3.3g) is dissolved in 100 cc of methanol and 9.1g of 4-~2-thienyl)-4-oxocrotonic acid is added. To the resulting solution is added 2g 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% HCl and a precipitate forms. It is filtered and air-dried to yield 8.lg of the title compound, melting point 163-165 C, dec. After recrystal-lization from ethanol the compound is constant melting at 171-173C, dec.

C) (+)-1-[3-(Acetylthio)-l-oxopropyl]-4,5-dihydro-
3-(2-thienyl)-lH-pyrazole-5-carboxylic acid (+)-4,5-Dihydro-3-(2-thienyl)-lH-pyrazole-5-carboxylic acid is dissolved in aqueous Na2CO3 (1.38g) at pH 8.6. The temperature is lowered to 5C and 3-(acetylthio)pro-pionyl chloride (4.15g) and a 25% solution of Na2CO3 are added simultaneously maintaining the pH at 8-9. The ~inal pH is 8.9 and -15~ 219/199 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%
5 HCl and the gurnmy 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 S.lg of material, melting point 127-130C, dec.
10 After recrystallization from CH3CN (very soluble) the melting point is constant at 134-136C, dec.

D) (+)-4,5-Dihydro-1-(3-mercapto-1-oxopropyl)-3-(2-thienyl)-lH-pyrazole-5-carboxylic acid _. _ (+)~ 3-(Acetylthio)-l-oxopropyl]-4,5-dihydro-3- (2-thienyl)-lH-pyrazole-5-carboxylic acid (4.7g) is added to a cooled solution of aqueous ammonia (12 cc) and stirred at 10C under nitrogen for 2 hours. A clear solution forms after about 10 20 ~inutes stirring. The aqueous layer is washed with ethyl acetate (discarded) and the aqueous layer made strongly acid with 20% HCl in the presence of ethyl acetate. The aqueous layer is extracted with two add'l 150 cc portions of ethyl 25 acetate and the combined organic layers dried over MgSO4. The solvent is removed yielding 3.2g of product, melting point 138-140C.
Analysis calc'd for Cl1H12N2O3S2: 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%

1 1 562 36 11~ 21Sfl99 Example_3 (+)-3-(2-Thienyl)-4,5-dihydro-1-[D,L-3,3,3-trifluoro-. . _ . _ . . . _ 2-(mercaptomethyl)-1-oxopropyl]-lH-pyrazole-5-carboxylic acid A) D,L-[3,3,3-Trifluoro-2-[4-(methoxy)benzylthio-methyl]]propionic acid A neat mixture of 3.9g of 2-(trifluoromethyl) acrylic acid [prepared according to the procedures described in J. Med. Che~., 7,3 (1964) and J. Chem.
Soc., 1371 (1954)] and 4.3g of 4-methoxybenzylthiol is stirred at 100-110C for one hour. The mixture solidifies at room temperature. Recrystallization from cyclohexane affords 6.8g of the title compound, melting point 72-74C.

B) (+)-4,5-Dihydro-l-(benzyloxycarbonyl)-3-(2-thienyl)-lH-pyrazole-5-carboxylic acid .
To a stirred mixture of 9.8g of (+)-4,5-dihydro-~-(2-thienyl)-lH-pyrazole-5-carboxyiic acid (see example 2B) and 13.8g of potassium carbonate in 8Oml of water and 4Oml of acetone there is added slowly 9.3g of benzyl chloroformate dissolved in 50ml of acetone, maintaining the temperature of the mixture at 10-15C with 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 HCl and cooled and filtered to obtain the title compound.

;:

1 156236 H~219/199 C) (+)-4,5-Dihydro-l-(benzyloxycar~onyl)-3-~2-thienyl)-lH-pyrazole-5-carboxylic acid,t-butyl ester A mixture of 6.6g of ~+)-4,5-dihydro-1-(benzyloxycarbonyl)-3-(2-thienyl)-lH-pyrazole-5-carboxylic acid, 5ml of isobutylene, 25ml of ether and 0.25ml of concentrated sulfuric acid is shaken in a pressure vessel for about 16 hours.
The reaction vessel is vented (-10C) and the contents are washed with ice cold aqueous ~odium 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)-lH-pyrazole-5-lS carboxylic acid, t-butyl est~r A solution of 5.0g of (+)-4,5-dihydro-1-(bezyloxycarbonyl)-3-(2-thienyl)-lH-pyrazole-5-carboxylic acid, t-butyl ester in 75ml of ethanol containing 0.5g of 5~ palladium on carbon is h~ydrogenated at atmospheric pressure until the uptake of hydrogen ceases. The catalyst is removed by filtration through Celite and the filtrate is concentrated in vacuo to yield the title compound.

E) (+)-3-(2-Thienyl)-4,5-dihydro-1-l3,3,3-trifluoro-2-[4-(methoxy)benzylthiomethyl]-1-oxopropyl]-lH-pyrazole-S-carboxylic acid, t-butyl ester ~ mixture of 2~94 g of D,L-13,3,3-trifluoro-2~4-(methoxy)benzylthiomethyl]]propionlc acid and 2.52 g of (+)-4,5-dihydro-3-(2-thienyl)-lH pyrazole-5-carboxylic acid, t-butyl ester in 500ml of 115623B ~A219/199 dichloromethane is stirred at 0C and treated with 2.06 g of dicyclohexyl carbodiimide. ~fter 30 minutes the cooling bath is removed and stirrin~
is continued at ambient temperature for about 16 hours. Solids are removed by filtration and the 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]-lH-pyrazole-5-carboxylic acid A solu~ion of 3.6 g of (+~-3-(2-thienyl)-
4,5-dihydro-1-[3,3 r 3-trifluoro-2-[4-(methoxy)-benzylthiomethyl]-1-oxopropyl-lH-pyrazole-5-carboxylic acid t-butyl ester and lOml of anisole is cooled to 0C in an ice bath and lOOml of trifluoroacetic acid is added, followed by 2.3 g ~ 20 Qf mercuric acetate. The bath is removed and ;~ the mixture is stirred at ambient temperature for one hour. After concentration ln ~acuo, the residue is triturated with ether/~entane 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.

. ~

1 1~6236 ~ 2lg/l99 Example 4 (~)-3-(2-Pyridyl)-4,5-dihydro-1-(3-mercapto-1-.
oxopro~yl)-lH-pyrazole-S-carboxylic acid A) 4-(2-Pyridyl)-4-oxo-2-butenoic acid, methyl es~
A solution of 33.4 g of carbomethoxymeth~lene triphenylphosphine IHelv. Chim. Acta. 40, 1242 (1957)] in SOOml of dry benzene under nitrogen is treated with 10 g of 2-(bromoacetyl)~yridine and heated at reflux temperature for 2 hours. The reaction mixt~re is cooled and filtered to remove carbomethoxymethyl triphenylphosphonium bromide.
The filtrate, containing triphenylphosphine, is treated with methyl bromoacetate and heated at lS reflux temperature for 2 hours. Cooling and filtration removes additional phosphonium salt.
The filtrate is concentrated ln vacuo yielding the title compound.

~ (2-Pyridyl)-4-oxo-2-butenoic acld , , .
A mixture of lS g of 4-(2-pyridyl)-4-oxo-2-butenoic acid, methyl ester in chloroform (50ml) is stirred with 3.14 g of sodium hydroxide in SOml of water for 5 hours at room temperature.
The aqueous layer is se2arated, washed with chloroform and acidified with 4.71 g of acetic acid, yielding the title compound.

1 156~36 HA219/199 C) ( )-3-(2-Pyridyl)-4,5-dihydro-lH-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 reflux temperature for 5 hours. Solvent is removed ln vacuo and theresidue is dissolved in 50 ~1 of water and treated with 3.0 g of acetic acid yieldin~
the title compound, D) (+)-1-[3-(Acetylthio)-l-oxopropyl]~3-(2-pyrid~ 4~5-dihydro-lH-p~razole-5-carboxylic acid (i)-3-(2-Pyridyl)-4,5-dihydro-lH-pyrazole-5-carboxylic acid (3.82 g) is dissolved in lOOml ofwater containing 2.12 g of sodium bicarbonate at 10C. 3-(Acetylthio)propionyl chloride (3.9 g) in 15ml of ether and 20% sodium carbonate solution are added simultaneously; the pH is maintained ~etween 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 i~ acidified with acetic acid and extracted with ethyl acetate three times. The solvent is dried over anhydrous magnesium sulfate and concen-trated ln vacuo, yielding the title compound.

1 156236 HA219~199 E) (+)-3-(2-Pyridy~ 4-~5-dihydro~ 3-mer-a~t l-oxopropyl)-lH-pyra201e-5-carboxylic acid Aqueous am~onia (12ml of 7N) is stirred at 0-5C under argon and 3.5 g of (+)-1-[3-(acet~l-thio)-1-oxopropyl]-3-(2-pyridyl)-4,5--dihydro-lH-pyrazole-5-carboxylic acid i6 added. The resulting solution is stirred for 2 hours under ar~on and is then extracted with ethyl acetate (discarded).
The aqueous layer is acidified with acetic acid and extracted with ethyl acetate (three SOml portions). The combined organic layers are washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated ln 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 for 3-~acetylthio)propionyl chloride, yields the compound of column III.

1156236 ~IA 219/199 O ~ X :~
~ h~rlI O .C
s I ~a u~ I ~ U
~ ~ 0~--~ I h ~.) I
I I sI ~ ~ e~
O I t~ U~ ~ I U I I I U
h X ~ t I ~ O
I ~) ~1 -- I I ~O ~ ~ I E r-~
-- ~ I U O ~ U :~Ll Q) S I -- O I U
1- O S ~ 1 I ' XO E~ ~) C) o ~ o ~-1 'r O ::~ O ~ .a h--I
i E. OS
~ I C X ~ , _ h~ S I . N ~ ~1 ~1 X
E ~, ~ ~,q O o ~ Us~ h ~ I -I.Q
_ ~ ~r ~' Ll N h 1~ 1 h , a) I ~ c ~ 1 I N ~ ~:1, a) I I ~
C U ~ O ~ I~) S:: I I U ~ U~ U
I I ,4 x ~ aJ o 5~1 (~1 ~ ` I
-- '~ I ~ -- ~--I1~ Q h ~1 `-- ~,~r ul ~ o ~ N~ ~ ~ ~ rl ~ O _ --' h S ~ J~ X r! ~1 U --' h ~
~ ~ O I _I O hI O ~ O
--I O ~ N ~I ~~1 S r~ O C N
I X ~a I S O ~ U I X ~ (a -- O I h -- IJ ~1 1 ~ a) ~ ~ o h +~ I ~ ~ +1 a~ 1 +I E3 ' ~ ~ +1 1 :
~ E' U _I_ _ ~" ,~, ~ ._ :, I
,~
~ S
S ,~
I ~ a) E. O
I ~a ~ ~ ~ o I ~
H ~Hrl 1 I N rl~ ~1 H I ~ ^ ~ O ~ Q- I h -- O O ~ h ~ O -- O
1: O ~1 ~ ~ O ,4 hO ~1 E' -1 S S O ~ 1 S
.C U JJ~ r~ S U
JJ ~ ~, ~ X ~1 O _~ _I ~ O ~1 0 ~ ~--o h au h S S ,~
N ~,~ JJ ~ ~ ~~ C
~ o c ~ ~ a) o `' Ur~ ~ E~ E~ h U--l ,a Ql Q S O `-- O On~ Q
-- O -- ~ I _ o C) ~ '--~ U
" ~ o a) ; C
a~
S S,~
O O f~ C
.C S ~ h H r-l ~ S O
e ~ v ~ ~ S ~ ~
~ e u e u o ~) ~ U~ ~ I
~, ~ ~, I
o ~, E3 o U U U h 1 1 56236 ~219/199 Exdmples 9-12 Following the procedure of Example 4, but substitutin~ the compound of column I for 2-(bromoacetyl)pyridine and the compound of S column II for 3-(acetylthio)propionyl chloride, yields the compound of column III.

~IA219/ 199 --2'1--U ~ ~ o U~
e ~ ~ E ~
I _ II :~ OI S 1 4 0 O
~ U~1 Q~ Nt'`l V C~ ~ h N
0 ~ ~ a) ~ a, a) ~
I a, O I h ~ I F. O I E h H ~ O ~~ a. ~_~ ~ N
H I ~ ~0 I O Q~ I ~r 111 1 ~ Q-H o ai ~ o x I ~ o--h o ~
o ~~ o ~1 I ~ O ~ ~) Q~
E ~ O I ":1~1 1 ~ ~ I I ~ _1 1 1 ~ S I ~ 1 r I -- S--~ 1 S O--_~ ~ rl O ~~ h ~ C~
o ~ I I ~ ~ ~ :~' ~ ~ I ,a I ~ ~-~1 X ~ I ~ X
O ~ O ~ r-l ~1 ~ O O
a~ ,~ ~I ~ a~ I x-,l :~ I I x p X -- E I h -- O h X ~ u~ o ~i o +~ a +1 1 :~ o +~
--~ Q~ ~-- U --~I Q~ 1 U

_I I
~ _I

H I ~a I ~ >
H
I h I ~ O .4 ~:: _ o -- O ~ --~ ~0 ~ O ~ ~ ~0 _l S ~) S C) O ~1 V .,1 ~) ~ N
O C O
~ a~ ~ Q~ a~ O a~ O
_ o -- O U ~
I S

O
~5 ~ S O
H h ~ ~ S
Q. Q.
_ ~ ~r ~ ~ ~ I I
:~
o ~ a tJ
O O
O O ~ ~ ~O ~:
0 ~ 0 4-,~
.a h I ~ I ~
~r ~ Q~ ~`I Q, o ,~
~ , Examvle 13 [l~S),5S]-4,5-~ihydro-1-[3-(acetylthio)_-2-methyl-1-oxopropy~ H-pyrazole-5-carboxylic acid A) Dlethyl-3,4-dlhydro-5H-~yrazole-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 _ vacuo to give 32.5 g of the title compound as an oil.
Analysis calc'd for CgH14N2O4: C,50.45; H,6.58;
N,13.08 Found: C,50.34; H,6.61; N,12.90 B) Diethyl-4,5-dihydro-lH-pyrazole-5,5-.
dicarboxylic a id, 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 90-94C.
Analysis calc'd for CgH14N2O4.HCl: C,43.12t H,6.03 N,11.17 Found: C,43.17; H,6.08; N,11.21 ~ 19/199 C) 4,5-Dihydro-lH-pyrazole-5-carboxylic acid A solution of 18.5 g of diethyl-4,5-dihydro-lH-pyrazole-5~5-dicarboxylic acid, hydrochloride salt in 72 ml of 1.07N hydrochloric acid is stirred and heated at 70-75C (oil bath) until evolution of carbon dioxide ceases (6 hours). The solution is cooled, and the water evaporated Ln vacuo to give 12.0 g of a viscous residue.
To remove the HCl 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 slgnifi-cantly 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 (Merck 2 mm) and developed in methanol (6 hours)~
Of the three W absorbing areas detected, the ; center portion contains the desired product, which is obtained by methanol e.xtraction to give 3.45 g of the title compound as an oil.

' 1156~36 ~ 219/199 D) [l(S),5S~-4,5-Dihydro-1-[3-(acetvlthio)-2-methyl-l-oxopropyl]-lH-pyrazole-5-carboxylic acid The above amino acid is combined with 1.55 g of similarly derived product and dissolved in 40 ml S of water. The pH is raised to 8.0 using lN 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 HCl to pH 2Ø 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 8Ø 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 ;~ 25 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.

ili~219/199 A small amount of tllis material is dissolved in ethyl acetate and treated with an equivalent amount of l-adamantanamine. Conversion of the resulting salt back to 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 l-adaman-tanaminç. The amine salt immediately precipitates to give 13.1 g of colorless material, melting point 167-169 C ~]D = -42 (MeO~). 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 tl3.1 g) is then dissolved in 25 ml of 3N HCl and extracted twice with CHC13. 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 lS 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 W 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 170-175C. Both products are obtained by methanol extraction.
Elemental analysis of the above solid shows it to be the adamantana~line salt of the acid. A
solution of this material in 9 ml of 3N HCl at room temperature gradually forms 0.84 g of a color-less solid, melting point 100-102C [~20 = -180(MeOH).

115623B ~ 219/lg9 This materlal is treated with 6 ml of not 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 15 ml of ether and cooled at 5C for 3 hours to give 0.04 g of solid, melting point 240-245C. The filtrate from the above purification is evaporated in vacuo to yield 0.70 g of a colorless solid, melting point 100-102; ~]20= -183 (MeOH). Crystallization from 4.5 ml of hot water yields 0.56 9 of desired product, ~elting point 104-106 ; ~]20 ~ -205 (MeOH).
Analysis calc'd for CloH14N2O4S H2O: C, 43.46; H, 5.83;
N, 10.14 Found: C, 43.91; H, 5.74; N, 9.96 Example 14 tl(s)~5s]-4~5-Dihydro-l-(3-mercapto-2-meth oxopropyl)-lH-pyrazole-5-carboxylic acid A solution of 0.56 g of [l(S),5S]-4,5-dihydro-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-lH-pyrazole-5-carboxylic 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 5C. This material is dried ln vacuo at 85C
for several hours to remove a moderate amount of NH4Cl. Tlle yield of product is 0.28 g, melting point 108-110 C, [~]20 = -171.
Analysis calc'd for C8H12N2O3S; 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 . 1 156236 ~1~219/199 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.

1l~2l9~l99 _I ~ tJ
O -~
~ b ~D " ~
O :C I ;) I D I X
~ o u- m I ~ ~ O
_, ,_ ~, -- I .a '--^ O ~ I 0 N I S
I V ~ _I O U~
I s ~
~ v 4 " I OQ' ra E ~ a x o :~ o ~ ~ 0 ~1 S ~ I ~ ~ S I r~
~0 ~ ~ x ~
1 S ~ I O .~ I --I I
h Ul 0 ` c:. ~ ` s r-l 1~ t~ I X t~ ' S D
` ' ~ a ^ ' ~o ^ ' ~
U~ O 4 ~ U~ O N U~ O D~
s ~ s ~ - cl O O
~1 ~
~o n, V
~ ~ o a~
JJ O .,1 --_I C~
I '- O
tJ ~ I
a, _I ^ O
O ::~ O
s .Ç V -r~
V r1 V ~
O
O ~ O --I
V N ~S:
D S:~ ~D ~ C t.i _ ~ 0 ~
I S I O I r .. ~ ~ ~ O
b ~ a So a ~
~D
.: r s.~ J~
SV ~
~) N N
O ~ ~
N ,1 "
~rl ~ ~a .-1 1 L
_1 , ~ ~1 2l9/l99 Example 18 [l(S),SSJ-4,5-Dihydro-1-[3-(acetylthio)-2-methyl-l-oxopropyll-5-methyl-lH-pyra2O1e-5-carboxylic acid A) MethyL-3,4-dihydro-5-methyl-5H-pyrazole-5-carboxylic acid ~ 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 ln 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 sin~le spot at Rf=0.34, visualized with phospho-molybdic acid plu5 heat. The oil has the following s~ectral characteristics: NMR( C,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), 5.78~(CO2CH3),
6.5~(N=N).

C~3 .' .
B) Methyl-4,5-dihydro-5-methyl-lH-prazole-5-carboxylic acid A solution of 0.5 g of methyl-3,4-dihydro-5-methyl-5H-pyrazole-5-carboxylic acid in 10 ml of ether is treated with gaseous hydrogen chloride, rapidly forming an amorphous precipitate. After cooling for about 16 hours at 5C, ether is decanted and the residue is washed several times with ether. l'he residue is dissolved in water, 2l9/199 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 S of product as an oil.
The original ether washes are washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 260 mg of product identical to the 60 m~ obtained above. Examination of the combined product on thin layer chromatography silica qel 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:
- N~5R( 3C,CDC13,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).

HN ~ C2CH3 : 5 C) 4,5-Dihydro-5-methyl-lH-prazole-5-carboxylic acid __ A solution of methyl-4,5-dihydro-5-methyl-lH-pyrazole-5-carboxylic acid in chloroform is stlrred with lN 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 2l9/l99 -3~-water until neutral and the product is then el~ted with 3N ammonium hydroxide. Evaporation in vacuo yields the title compound.

D) [l(S),SS]-4,5-Dihydr -1-[3-(acetylthio)-2-methyl-l-oxopropyl]-5-methyl-lH-pyrazole-S-carboxylic acid Following the procedure of Example l~, but substituting 4,5-dihydro-S-methyl-lH-pyrazole-5-carboxylic acid for 4,5-dihydro-lH-pyrazole-5-carboxylic acid, yields the title compound.

Claims (20)

What is claimed is:
1. A process for preparing a compound of the formula wherein: Rl is hydrogen, benzyl which may be substituted with alkoxy containing 1 to 3 carbon atoms and alkanoyl containing 2 to 4 carbon atoms;
R2 is hydrogen and alkyl containing 1 to 3 carbon atoms;
R3 is hydrogen, furanyl, thienyl and pyridyl;
R4 is hydrogen and alkyl containing 1 to 8 carbon atoms;
R5 is hydrogen and alkyl containing 1 to 3 carbon atoms; and n is 1 or 2;
characterized by reacting an amino acid having the formula with a mercaptoacyl halide of the formula wherein R1 is benzyl or alkanoyl as previously defined for R1 and X is chloro or bromo, to form products wherein Rl is benzyl or alkanoyl as defined and R4 is hydrogen and hydrolyzing said product wherein Rl is alkanoyl to form a product wherein R1 is hydrogen and then treating these products with a Cl to C8 diazoalkane or alcohol to form a product wherein R4 is Cl to C8 alkyl.
2. A process according to claim 1 wherein Rl is hydrogen.
3. A process according to claim 1 wherein Rl is alkanoyl containing 2 to 4 carbon atoms.
4. A process according to claim 1 wherein R2 is methyl.
5. A process according to claim I wherein R4 is hydrogen.
6. A process according to claim L wherein R5 is hydrogen.
7. A process according to claim 1 wherein n is 1.
8. A process according to claim L wherein 4,5-dihydro-3-(2-thienyl)-lH-pyrazole-5-carboxylic acid is reacted with 3-(acetylthio)propionyl chloride to form 1-[3-(acetylthio)-l-oxopropyl]-4,5-dihydro-3-(2-thienyl)-lH-pyrazole-5-carboxylic acid.
9. A process according to claim 1 wherein 4,5-dihydro-lH-pyrazole-5-carboxylic acid is reacted with D-3-(acetylthio)-2-methylpropionyl chloride to form [l(S),5(S)]-4,5-dihydro-l-[3-(acetylthio)-2-methyl-1-oxopropyl]-lH-pyrazole--5-carboxylic acid.
10. A process according to claim l wherein 3-(2-furanyl)-4,5-dihydro-lH-pyrazole-5-carboxylic acid is reacted with 3-(acetylthio)propionyl chloride to form l-[3-(acetylthio)-l-oxopropyl]-3-(2-furanyl)-4,5-dihydro-lH-pyrazole-55-carboxylic acid.
11. A compound of the formula wherein: Rl is hydrogen, benzyl which may be substituted with alkoxy containing l to 3 carbon atoms and alkanoyl containing 2 to 4 carbon atoms;
R2 is hydrogen and alkyl containing l to 3 carbon atoms;
R3 is hydrogen, furanyl, thienyl and pyridyl;
R4 is hydrogen and alkyl containing 1 to 8 carbon atoms;
R5 is hydrogen and alkyl containing l to 3 carbon atoms; and n is l or 2, whenever prepared by the process of claim l.
12. A compound according to claim 11 wherein Rl is hydrogen, whenever prepared by the process of claim 2.
13. A compound according to claim 11 wherein Rl is alkanoyl containing 2 to 4 carbon atoms, whenever prepared by the process of claim 3.

HAl99/2l9
14. A compound according to claim 11 wherein R2 is methyl, whenever prepared by the process of claim 4.
15. A compound according to claim 11 wherein R4 is hydrogen, whenever prepared by the process of claim 5.
16. A compound according to claim 11 wherein R5 is hydrogen, whenever prepared by the process of claim 6.
17. A compound according to claim 11 wherein n is 1, whenever prepared by the process of claim 7.
18. A compound according to claim 11 wherein the product is1-[3-(acetylthio)-1-oxopropyl]-4,5-dihydro-3-(2-thhienyl)-lH-pyrazole-5-carboxylic acid, whenever prepared by the process of claim 8.
19. A compound according to claim 11 wherein the product is[l(S),5(S)]-4,5-dihydro-1-[3-(acetylthio)-2-methyl-1-oxo-propyl]-lH-pyrazole-5-carboxylic acid, whenever prepared by the process of claim 9.
20. A compound according to claim 11 wherein the product is1-[3-(acetylthio)-1-oxopropyl]-3-(2-furanyl)-4,5-dihydro-lH-pyrazole-5-carboxylic acid, whenever prepared by the process of claim 10.
CA000361332A 1979-10-25 1980-10-01 Mercaptoacyldihydropyrazole carboxylic acid derivatives Expired CA1156236A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US06/088,425 US4254267A (en) 1979-10-25 1979-10-25 Mercaptoacyldihydropyrazole carboxylic acid derivatives
US88,425 1979-10-25
US06/140,355 US4266065A (en) 1980-04-14 1980-04-14 Mercaptoacyldihydropyrazole carboxylic acid derivatives
US140,355 1980-04-14

Publications (1)

Publication Number Publication Date
CA1156236A true CA1156236A (en) 1983-11-01

Family

ID=26778642

Family Applications (1)

Application Number Title Priority Date Filing Date
CA000361332A Expired CA1156236A (en) 1979-10-25 1980-10-01 Mercaptoacyldihydropyrazole carboxylic acid derivatives

Country Status (5)

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

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE454355B (en) * 1983-01-24 1988-04-25 Roussel Uclaf ACRYLIC ACID DERIVATIVES CONTAINING A FURYL, PYRANYL, BENZOFURANYL, OXAZOLYL OR ISOXAZOLYL GROUP, PROCEDURES FOR PREPARING THEREOF, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEMSELVES
IT1179503B (en) * 1984-07-20 1987-09-16 Roussel Maestretti Spa New 4-furyl-4-oxo-butenoic acid derivs.

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

Also Published As

Publication number Publication date
GB2129420A (en) 1984-05-16
GB2129420B (en) 1984-10-31
FR2474494B1 (en) 1983-06-17
DE3040258A1 (en) 1981-05-21
GB8300874D0 (en) 1983-02-16
GB2061934A (en) 1981-05-20
IT1134037B (en) 1986-07-24
GB2061934B (en) 1984-06-06
FR2482099A1 (en) 1981-11-13
FR2474494A1 (en) 1981-07-31
IT8025575A0 (en) 1980-10-24
FR2482099B1 (en) 1983-09-30

Similar Documents

Publication Publication Date Title
US4316905A (en) Mercaptoacyl derivatives of various 4-substituted prolines
US4468519A (en) Esters of phosphinylalkanoyl substituted prolines
US5319099A (en) 3-benzylidene-1-carbamoyl-2-pyrrolidone compounds useful as antiinflammatory agents
US4154935A (en) Halogen substituted mercaptoacylamino acids
US4234489A (en) Pyroglutamic acid derivatives and analogs
US5981525A (en) Indole derivatives useful in the treatment of osteoporosis
US4296113A (en) Mercaptoacyl derivatives of keto substituted proline and pipecolic acid
ES2217882T3 (en) 4- (AMINOALCOXY) BENZOFURANS AS INHIBITORS OF N-MIRISTOILTRANSFERASA.
JPS5834474B2 (en) Method for producing thiazolidine derivatives
US5348969A (en) Diphenyloxazolyl-oxazoles as platelet aggregation inhibitors
US4296033A (en) 4-Azido-1-mercaptoacyl proline
US4211786A (en) Mercaptoacyldihydropyrazole carboxylic acid derivatives
AU2009263076B2 (en) New heterocyclic carboxamides for use as thrombin inhibitors
FR2566404A1 (en) NOVEL 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR SALTS, PROCESS FOR THEIR PREPARATION, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US4254267A (en) Mercaptoacyldihydropyrazole carboxylic acid derivatives
CA1156236A (en) Mercaptoacyldihydropyrazole carboxylic acid derivatives
GB2122605A (en) Mercaptoacyl derivatives of prolines
US4450275A (en) Cyclic iminocarboxylic acid derivatives
DE2828578C2 (en) Thiazolidines, their manufacture and use
US4266065A (en) Mercaptoacyldihydropyrazole carboxylic acid derivatives
US4312809A (en) Lactam derivatives of mercaptoacylamino acids
US4312990A (en) 1-Mercaptoacyl-3-[(aminosulfonyl) phenyl]-4,5-dihydro-1H-pyrazole-5-carboxylic acid
US4221804A (en) Mercaptoacyldihydropyrazole carboxylic acid derivatives
DK141966B (en) Analogous process for the preparation of penicillin compounds or salts or hydrated forms thereof.
US4322541A (en) Dihydropyrazole-5-carboxylic acid and analogs

Legal Events

Date Code Title Description
MKEX Expiry
MKEX Expiry

Effective date: 20001101