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HK1074204B - Pyrrolidine oxadiazole-and thiadiazole derivatives - Google Patents

Pyrrolidine oxadiazole-and thiadiazole derivatives Download PDF

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Publication number
HK1074204B
HK1074204B HK05108106.9A HK05108106A HK1074204B HK 1074204 B HK1074204 B HK 1074204B HK 05108106 A HK05108106 A HK 05108106A HK 1074204 B HK1074204 B HK 1074204B
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HK
Hong Kong
Prior art keywords
biphenyl
oxadiazol
pyrrolidinone
ylcarbonyl
methyl
Prior art date
Application number
HK05108106.9A
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Chinese (zh)
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HK1074204A1 (en
Inventor
M‧施瓦兹
P‧佩奇
V‧珀梅尔
A‧夸特罗帕尼
R‧J‧托马斯
Original Assignee
默克雪兰诺有限公司
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Priority claimed from PCT/EP2002/006629 external-priority patent/WO2002102799A2/en
Publication of HK1074204A1 publication Critical patent/HK1074204A1/en
Publication of HK1074204B publication Critical patent/HK1074204B/en

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Description

pyrrolidine oxadiazole and thiadiazole derivatives
Technical Field
The present invention relates to novel pyrrolidine oxadiazole and thiadiazole derivatives, in particular these compounds for use as medicaments, and pharmaceutical formulations comprising these pyrrolidine derivatives. Said pyrrolidine derivatives are useful for the treatment and/or prevention of preterm labor, premature birth and dysmenorrhea.
Preferably the pyrrolidine derivatives have modulating, in particular antagonistic, activity towards the oxytocin receptor. More preferably, the compounds are useful for the treatment and/or prevention of diseases mediated by oxytocin, including preterm labor, premature labor and dysmenorrhea.
Background
In the field of obstetrics, one of the most important issues is the control of miscarriage and preterm birth, as they are the major causes of perinatal morbidity and mortality.
The use of magnesium sulfate with ethanol has been suggested for the treatment of abortion. However, plasma concentrations of magnesium sulfate in excess of the therapeutic range of 4 to 8mg/dL can cause inhibition of cardiac and neuromuscular conduction, respiratory depression and cardiac arrest, and thus the formulation is not suitable for use particularly in persons with impaired renal function.
Ethanol is effective in preventing premature delivery, but it does not correspondingly reduce the incidence of fetal respiratory distress. Also, ethanol is thought to have adverse effects on the fetus.
The other two therapeutic agents belong to any one of the following groups:
a) a beta 2-adrenergic agonist, or
b) An oxytocin antagonist.
The β 2-adrenoreceptors usually cause an inhibitory effect on the cells inside the organs (muscle, heart, uterus, etc.) in which they are expressed. Beta 2-adrenergic agonists are used to activate the inhibitory effect of the receptor. Thus, β 2-adrenergic agonists are sympathomimetic agents-in particular-inhibit uterine contractility. Known beta 2-adrenergic agonists for the treatment of abortion are ritodrine, terbutaline and albuterol.
Ritodrine (i.e. (R, S) -4-hydroxy-alpha- [1- [ [2- (4-hydroxyphenyl) ethyl group)]-amino group]-ethyl radical]-benzyl alcohol; see US3,410,944 to n.v. philips) is a leading beta2Adrenergic agonists, but cause many cardiovascular and metabolic side effects in the mother, including tachycardia, increased renin secretion, hyperglycemia (and reactive hypoglycemia in infants).
Metadroxytertbutylphenaline (i.e. 5- [2- (1, 1-dimethylethyl) amino ] -1-hydroxyethyl ] -1, 3-benzenediol, U.S. Pat. No. 3,937,838 to Draco and albuterol (. alpha.' -1- [ [ (1, 1-dimethylethyl) amino ] -methyl ] -4-hydroxy-1, 3-benzenedimethanol; Allen and U.S. Pat. No. 3,644,353 to Hanburys) is another β 2-adrenergic agonist and has side effects similar to ritodrine.
A more recent method of treating miscarriage involves the use of oxytocin antagonists.
Oxytocin (OT) is a peptide hormone that causes uterine contractions during the childbirth process in mammals. Corresponding oxytocin receptor and V1aAnd V2The vasopressin receptor similarly functions by interacting with G-protein coupled receptors which in turn are activated by phospholipase C and, in turn, by Ca released from intracellular stores2+IP of3Is correlated with the increase in (c). The concomitant increase in intracellular calcium leads to increased smooth muscle contraction through activated myosin light chain kinase. Oxytocin (OT) receptors are significantly increased during pregnancy. The concentration of OT receptors has been shown to be associated with spontaneous uterine activity. (M.Maggi et al. J.Clin.Endocrinol Metabol; 70; 1142, 1990). In recent years, evidence has accumulated strongly suggesting that this oxytocin hormone may be the physiological initiator of labor in a number of mammalian species, including humans. Furthermore, oxytocin is believed to play this role in two distinct aspects:
by direct contraction of the myometrium of the uterus, and
by increasing the synthesis and release of prostaglandins with contractile properties in the uterus/decidua. In addition, these prostaglandins may be important during cervical maturation.
By these mechanisms, the process of labor (pregnancy completion and preterm birth) is stimulated by increasing the sensitivity of the uterus to oxytocin, in part as a result of the increased number of receptors in this tissue.
By blocking oxytocin, it is possible to achieve both direct (contractile) and indirect (increased prostaglandin synthesis) effects of oxytocin on the uterus. Thus oxytocin blockers or antagonists are considered more effective than current therapies for treating miscarriage.
Atosiban (i.e., oxytocin, 1- (3-mercaptopropionic acid) -2- (O-ethyl-D-tyrosine) -4-L-threonine-8-L-ornithine) is a cyclic pentapeptide, the best known OT antagonist (WO9501368, Ferring A B; J.reprod.Fertil., 101 (2)), 345-52(English) 1994; am.J.Obstet.Gynecol., 170 (2)), 474-8(English) 1994). The major disadvantage of using peptide antagonists like atosiban is the problem of overcoming the low bioavailability caused by intestinal degradation. Therefore, they must be administered parenterally.
Furthermore, WO96/22775 and US5,756,497 (Merck) disclose benzoxazinylpiperidine or benzoxazinone-based compounds as OT receptor antagonists. Indanylpiperidine and tolylpiperazine compounds are reported by Evans (Evans) et al in j.med.chem., 35, 3919(1992) as oral OT antagonists.
It has now been found that the compounds of the present invention are oxytocin antagonists and are capable of binding to the oxytocin receptor. When oxytocin receptors are bound together by the compounds of the present invention, oxytocin is antagonized by blocking it from its receptor and thus fails to exert its biological or pharmacological effects. The compounds of the invention are therefore useful in the treatment and prevention of abortion and premature birth. The compounds are also used for labor cessation prior to caesarean section. In particular, the compounds of the invention are useful for the treatment and prophylaxis of oxytocin-related animal diseases in mammals, preferably mammals, particularly preferably humans. It is another object of the invention to provide a method of antagonizing oxytocin function in a diseased mammal. It is another object of the present invention to develop a method for preventing or treating oxytocin-related miscarriage symptoms by antagonizing the binding of oxytocin to its receptor.
The compounds of the invention are also useful for the treatment of dysmenorrhea, a cyclic pain associated with menstrual blood during the ovulation cycle. The pain is thought to be caused by uterine contractions and ischemia, possibly mediated by the action of prostaglandins produced by the endometrium during the secretory phase. By blocking the direct and indirect effects of oxytocin on the uterus, oxytocin antagonists can treat dysmenorrhea more effectively than current therapies.
Disclosure of Invention
The following paragraphs provide definitions of the various chemical groups that make up the compounds of the present invention and have the same meaning throughout the specification and claims of this invention, unless a broader scope is otherwise defined.
“C1-C6-alkyl "means a monovalent alkyl group having 1 to 6 carbon atoms. The term exemplary group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and the like.
"aryl" refers to an unsaturated aromatic monocyclic (e.g., phenyl) or multiply fused (e.g., naphthyl) carbocyclic group containing 6 to 14 carbon atoms. Preferred aryl groups include phenyl, naphthyl, phenanthryl, and the like.
″C1-C6By alkylaryl "is meant C with an aryl substituent1-C6Alkyl groups including benzyl, phenethyl and the like.
"heteroaryl" refers to a monocyclic heteroaryl, or a bicyclic or tricyclic fused ring heteroaryl. Specific examples of heteroaryl groups include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-triazinyl, 1, 2, 3-triazinyl, benzofuranyl, [2, 3-dihydro ] -benzofuranyl, isobenzofuranyl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo [1, 2-a ] -pyridyl, benzothiazole, benzoxazolyl, quinolizinyl, quinazolinyl, 2, 3-naphthyridinyl (pthalazinyl), quinoxalinyl, cinnolinyl, naphtopyridinyl, pyrido [3, 4-b ] -pyridinyl, pyrido [3, 2-b ] -pyridinyl, pyrido [4, 3-b ] -pyridinyl, quinolinyl, isoquinolinyl, tetrazolyl, 5, 6, 7, 8-tetrahydroquinolinyl, 5, 6, 7, 8-tetrahydroisoquinolinyl, purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolinyl.
″C1-C6By "alkylheteroaryl" is meant C with a heteroaryl substituent1-C6Alkyl substituents including 2-furylmethyl, 2-thienylmethyl, 2- (1H-indol-3-yl) ethyl and the like.
″C2-C6-alkenyl "means alkenyl having 2 to 6 carbon atoms and having at least 1 or 2 ethylenic unsaturations. Preferred alkenyl substituents include vinyl (-CH ═ CH)2) N-2-propenyl (allyl, -CH)2CH＝CH2) And the like.
″C2-C6By alkenylaryl "is meant C with an aryl substituent2-C6Alkenyl groups including 2-phenylvinyl and the like.
″C2-C6By alkenylheteroaryl "is meant C with a heteroaryl substituent2-C6Alkenyl groups including 2- (3-pyridyl) vinyl and the like.
″C2-C6-alkynyl "means an alkynyl group having 2 to 6 carbon atoms and having at least 1-2 acetylenic unsaturations, preferred alkynyl groups include ethynyl (-C ═ CH), propargyl (-CH)2C ═ CH), and the like.
″C2-C6By alkynylaryl "is meant C with an aryl substituent2-C6Alkynyl substituents include phenylethynyl and the like.
″C2-C6By alkynylheteroaryl "is meant C with a heteroaryl substituent2-C6Alkynyl substituents including 2-thiophenylethynyl and the like.
″C3-C8-cycloalkyl "refers to a saturated carbocyclic group having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl) of 3 to 8 carbon atoms. Preferred cycloalkyl groups include cyclopentyl, cyclohexyl, norbornyl, and the like.
″C1-C6By alkylcycloalkyl "is meant C with a cycloalkyl substituent1-C6Alkyl groups including cyclohexylmethyl, cyclopentylpropyl and the like.
"Heterocycloalkyl" means a group C as defined above3-C8-cycloalkyl in which up to 3 carbon atoms are replaced by heteroatoms selected from O, S, NR (R is hydrogen or methyl). Preferred heterocycloalkyl groups include pyrrolidine, piperidine, piperazine, 1-methylpiperazine, 4-morpholinyl and the like.
″C1-C6By alkyl heterocycloalkyl "is meant C having a heterocycloalkyl substituent2-C6Alkyl groups including 2- (1-pyrrolidinyl) ethyl, 4-morpholinylmethyl, (1-methyl-4-piperidinyl) methyl and the like.
"carboxy" refers to the-C (O) OH group.
″C1-C6By "alkylcarboxy" is meant C having a carboxyl substituent1-C6Alkyl groups including 2-carboxyethyl and the like.
"acyl" refers to the group C (O) R, wherein R includes H, "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl ", heterocycloalkyl", "aryl", "heteroaryl", "C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6-alkenylaryl "," C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ".
″C1-C6-Alkylacyl "means C having an acyl substituent1-C6Alkyl groups including 2-acetoacetyl and the like.
"Arylacyl" refers to an aryl group having an acyl substituent, including 2-acetylphenyl and the like.
"heteroarylacyl" refers to a heteroaryl group having an acyl substituent, including 2-acetylpyridyl, and the like.
″C3-C8(hetero) cycloalkylacyl "refers to a 3 to 8 membered cycloalkyl or heterocycloalkyl substituent having an acyl substituent.
"acyloxy" refers to the substituent-OC (O) R, where R includes H, "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl ", heterocycloalkyl", "aryl", "heteroaryl", "C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6-alkenylaryl "," C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ".
″C1-C6-Alkylacyloxy "means a C group having an acyloxy substituent1-C6Alkyl groups including 2- (acetoxy) ethyl and the like.
"alkoxy" refers to the group-O-R, where R includes "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6-alkenylaryl "," C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-an alkynylheteroaryl',″C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ".
″C1-C6By "alkylalkoxy" is meant C with an alkoxy substituent1-C6Alkyl groups including 2-ethoxyethyl and the like.
"alkoxycarbonyl" refers to the group-C (O) OR, wherein R includes "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6-alkenylaryl "," C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ".
″C1-C6By alkylalkoxycarbonyl "is meant C with an alkoxycarbonyl substituent1-C6Alkyl groups including 2- (benzyloxyacyl) ethyl and the like.
"aminocarbonyl" refers to the group-C (O) NRR 'where each R, R' independently includes hydrogen, "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8Cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6-alkenylaryl "," C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ".
″C1-C6By "alkylaminocarbonyl" is meant a C having an aminocarbonyl substituent1-C6Alkyl groups including 2- (dimethylaminocarbonyl) ethyl and the like.
"amido" refers to the group-NRC (O) R ', wherein R, R' are each independently hydrogen, "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6-alkenylaryl "," C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ".
″C1-C6By "alkylamido" is meant C with an amido substituent1-C6Alkyl groups including 2- (propionylamino) ethyl and the like.
"ureido" means a radical-NRC (O) NR 'R "wherein each R, R', R" is independently selected from hydrogen, "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6-alkenylaryl "," C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ", and wherein R' and R" together with the nitrogen atom to which they are attached optionally form a 3-8 membered heterocycloalkyl ring.
″C1-C6By alkylureido "is meant C having a ureido substituent1-C6Alkyl groups including 2- (N' -methylureido) ethyl and the like.
"Carbamate" refers to the group-NRC (O) OR ', wherein R, R' are independently hydrogen, "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6Alkenyl aryl, "C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ".
"amino" refers to the group-NRR ', where each R, R' is independently hydrogen, "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6Alkenyl aryl, "C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ", and wherein R' and R" together with the nitrogen atom to which they are attached optionally form a 3-8 membered heterocycloalkyl ring.
″C1-C6By "alkylamino" is meant C with an amino substituent1-C6Alkyl groups including 2- (1-pyrrolidinyl) ethyl and the like.
"ammonium group" means a positively charged group N+RR ' R ', where each R, R ' is independently hydrogen, "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6-alkenylaryl "," C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ", and wherein R, R' together with the nitrogen atom to which they are attached optionally form a 3-8 membered heterocycloalkyl ring.
″C1-C6By "alkylammonium group" is meant C with an ammonium group substituent1-C6Alkyl groups including 2- (1-pyrrolidinyl) ethyl and the like.
"ionizable residue" refers to a residue that can be converted into a salt, for example, by protonation. Amino or sulfonyl residues are examples of ionizable/protonated residues.
"halogen" refers to fluorine, chlorine, bromine and iodine atoms.
"Sulfonyloxy" refers to the group-OSO2-R, wherein R is selected from hydrogen, "C1-C6-alkyl ", halo" C1-C6Alkyl radicals, e.g. -OSO2-CF3Radical, C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6-alkyl radicalAryl "or" C1-C6-alkylheteroaryl "," C2-C6-alkenylaryl "," C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ".
″C1-C6-Alkylsulfonyloxy "means C having a sulfonyloxy substituent1-C6Alkyl groups including 2- (methylsulfonyloxy) ethyl and the like.
"Sulfonyl" refers to the group "-SO2-R is wherein R is selected from the group consisting of hydrogen, "aryl", "heteroaryl", "C1-C6-alkyl ", halo" C1-C6-alkyl ", e.g. -SO2-CF3Group,' C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6- - -alkenylaryl "," C2-C6- - -alkenylheteroaryl "," C2-C6- - -alkynylaryl "," C2-C6- - -alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ".
″C1-C6-alkylsulfonyl "means C having a sulfonyl substituent1-C6Alkyl groups including 2- (methylsulfonyl) ethyl and the like.
"sulfinyl" refers to the group "-S (O) -R", wherein R is selected from hydrogen, "C1-C6Alkyl ', halo' C1-C6Alkyl "halo, e.g., -SO-CF3Group,' C2-C6-alkenyl "," C2-C6-alkynyl ","C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6- - -alkenylaryl "," C2-C6- - -alkenylheteroaryl "," C2-C6- - -alkynylaryl "," C2-C6- - -alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ".
″C1-C6-Alkylsulfinyl "refers to C having a sulfinyl substituent1-C6Alkyl groups including 2- (methanesulfinyl) ethyl and the like.
"Thioalkyl" refers to the group-S-R, where R includes hydrogen, "C1-C6Alkyl ', halo' C1-C6-alkyl ", e.g., -SO-CF3Group,' C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6- - -alkenylaryl "," C2-C6- - -alkenylheteroaryl "," C2-C6- - -alkynylaryl "," C2-C6- - -alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ". Preferred sulfanyl groups include methylthioalkyl, ethylsulfanyl and the like.
“C1-C6By alkylsulfanyl is meant having C1-C6The sulfanyl group of the alkyl substituent includes 2- (ethylsulfanyl) ethyl and the like.
"sulfonamido" refers to the group-NRSO2-R ', wherein each R, R' independently comprises hydrogen, "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6-alkenylaryl "," C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ".
″C1-C6By "alkylsulfonylamino" is meant C with a sulfonylamino substituent1-C6Alkyl groups including 2- (ethylsulfonylamino) ethyl and the like.
"aminosulfonyl" means the substituent-SO2-NRR ', wherein each R, R' independently comprises hydrogen, "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6-alkenylaryl "," C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ".
″C1-C6By "alkylaminosulfonyl" is meant C having an aminosulfonyl substituent1-C6Alkyl groups including 2- (cyclohexylaminosulfonyl) ethyl and the like.
"substituted or unsubstituted": unless a substituent is separately mandatory, the above groups, such as "alkyl", "alkenyl",the "alkynyl", "aryl" and "heteroaryl" groups may be optionally substituted with 1 to 5 substituents selected from the group consisting of: "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl ', "cycloalkyl '," heterocycloalkyl ', "C1-C6-alkylaryl "," C1-C6-alkylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkyl heterocycloalkyl "," amino "," ammonium "," acyl "," acyloxy "," amido "," aminocarbonyl "," alkoxycarbonyl "," ureido "," carbamate "," aryl "," heteroaryl "," sulfinyl "," sulfonyl "," alkoxy "," sulfanyl "," halogen "," carboxy ", trihalomethyl, cyano, hydroxy, mercapto, nitro and the like. Or the substitution may also comprise the closure of a ring by an ortho substituent, especially where a vicinal functional substituent is involved, to form a lactam, lactone, cyclic anhydride, or an acetal, thioacetal, aminal by closure of a ring, for example in the case of attempts to obtain a protecting group.
"pharmaceutically acceptable salt or complex" refers to a salt or complex of a compound of the formula defined below that retains the desired biological activity. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, methanesulfonic acid, and polygalacturonic acid. The compounds may also be administered in the form of pharmaceutically acceptable quaternary salts well known to those skilled in the art, including in particular those having the general formula NRR' R ″+Z-Quaternary ammonium salts of the structure in which R, R' are independently hydrogen, alkyl, or benzyl, C1-C6-alkyl radical, C2-C6-alkenyl radical, C2-C6-alkynyl, C2-C6-alkylaryl group, C1-C6-alkylheteroaryl, cycloalkyl, heterocycloalkyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, tosylate, mesylate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbic acid, cinnamate, mandelate, and diphenylacetate).
"pharmaceutically active derivative" refers to any compound that, upon administration to a recipient, provides, directly or indirectly, the activity described herein.
"enantiomeric excess" (ee) means that the product is obtained by asymmetric synthesis, i.e., synthesis involving non-racemic starting materials and/or reagents, or synthesis that includes at least one enantioselective step, such that an excess of at least about 52% ee is obtained for one of the enantiomers. However, where asymmetric synthesis is not used, the racemic product is typically obtained with the same activity as the OT-R antagonist of the present invention.
The compound of the general formula (I) of the invention also includes tautomers, geometrical isomers, optical isomers as enantiomers, diastereomers and racemates thereof, and pharmaceutically acceptable salts thereof and the like. Preferred pharmaceutically acceptable salts of formula (I) are acid addition salts with pharmaceutically acceptable acids, such as hydrochloride, hydrobromide, sulphate or hydrogen sulphate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulphonate, benzenesulphonate, and p-toluenesulphonate.
One aspect of the present invention is pyrrolidine oxadiazole and thiadiazole compounds of general formula (I).
Pyrrolidine oxadiazole and thiadiazole derivatives of general formula I are useful for modulating, in particular inhibiting, OT-R function, more particularly for antagonizing oxytocin receptors. When the nitrogen oxytocin receptor is combined with the compound of the formula I, the receptor is blocked to antagonize oxytocin, so that the compound can not exert the biological or pharmacological effect. The compounds of the invention are therefore also particularly useful for the treatment and/or prophylaxis of oxytocin-related disorders in mammals, particularly humans.
The compounds of the present invention are those of the general formula I.
The compounds of the general formula also include geometric isomers thereof, optically active forms as enantiomers, diastereomers and racemates thereof, and pharmaceutically acceptable salts thereof, and the like. Preferred pharmaceutically acceptable salts of compound I are the acid addition salts with pharmaceutically acceptable acids such as hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or hydrogenphosphate, acetate, benzoate, succinic acid, fumarate, maleate, lactate, citrate, tartrate, gluconate, mesylate (methanesulfonate), benzenesulfonate, and p-toluenesulfonate.
In the general formula (I), A is selected from- (C ═ O) -, - (C ═ O) -O, -SO2-，-SO2NH-，-C(＝NH)-，-(C＝O)-NH-，-(C＝S)-NH，-CH2-. Most preferably a is carbonyl.
B is an unsubstituted or substituted oxadiazole or thiadiazole ring.
R1Selected from: unsubstituted or substituted C1-C6Alkyl, unsubstituted or substituted C2-C6Alkenyl, unsubstituted or substituted C2-C6-alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C1-C6Alkylaryl, unsubstituted or substituted C1-C6-alkylheteroaryl, R1May be taken together with the O atom to which it is attachedForming a 3-8 membered substituted or unsubstituted, saturated or unsaturated heterocyclic ring which may further comprise 1-2 heteroatoms selected from N, S and O, and which is optionally fused to an aryl, heteroaryl and 3-8 membered saturated or unsaturated cycloalkyl ring. Preferably R1Is hydrogen or C1-C3Alkyl, most preferably methyl.
R2Selected from: unsubstituted or substituted C1-C6Alkyl, unsubstituted or substituted C2-C6Alkenyl, unsubstituted or substituted C2-C6-alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3-to 8-membered cycloalkyl, acyl, unsubstituted or substituted C1-C6Alkylaryl, unsubstituted or substituted C1-C6-alkylheteroaryl, said cycloalkyl or aryl or heteroaryl substituents possibly being further fused with 1-2 cycloalkyl or aryl or heteroaryl groups. More preferred is aryl, especially optionally substituted phenyl, for example further substituted with phenyl (thereby forming a biphenyl residue).
R3’R4’R5And R6Independently selected from hydrogen, halogen, C1-C6Alkyl radical, C1-C6-alkoxy groups. Preferably they are each H.
Preferred pyrrolidine derivatives are compounds of the general formula I, wherein R is1Selected from hydrogen or C1-C6Alkyl, especially-CH3A is- (C ═ O) -, R2Is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, in particular biphenyl.
According to a preferred embodiment, the substituent B is a 1, 2, 4-oxadiazole substituent, which may be attached to the pyrrolidine ring in the following manner (IIa) and (IIb):
in the general formulae (IIa) and (IIb), R7Selected from: hydrogen, sulfonyl, amino, unsubstituted or substituted C1-C6Alkyl, unsubstituted or substituted C2-C6-alkenyl, unsubstituted or substituted C2-C6-alkynyl, wherein the alkyl, alkenyl, alkynyl chain may be interrupted by heteroatoms selected from N, O or S, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl, unsubstituted or substituted heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl substituents may be further fused with 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups, an acyl residue, unsubstituted or substituted C1-C6Alkylaryl, unsubstituted or substituted C1-C6Alkyl heteroaryl, unsubstituted or substituted C1-C6Alkenylaryl, unsubstituted or substituted C1-C6Alkenylheteroaryl, unsubstituted or substituted C1-C6Alkynylaryl, unsubstituted or substituted C1-C6Alkynylheteroaryl, unsubstituted or substituted C1-C6Alkylcycloalkyl, unsubstituted or substituted C1-C6Alkyl heterocycloalkyl, unsubstituted or substituted C1-C6Alkenylcycloalkyl, unsubstituted or substituted C1-C6Alkenyl heterocycloalkyl, unsubstituted or substituted C1-C6Alkynylcycloalkyl, unsubstituted or substituted C1-C6Alkynyl heterocycloalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted C1-C6-alkylcarboxy, substituted or unsubstituted C1-C6Alkanoyl, substituted or unsubstituted aryloyl, substituted or unsubstituted heteroarylacyl, substituted or unsubstituted C3-C8(hetero) cycloalkylacyl, unsubstituted or substituted C1-C6-alkanoyloxy, unsubstituted or substituted C1-C6Alkyl alkoxy, unsubstituted or substituted C1-C6Alkyl alkoxycarbonyl, unsubstituted or substituted C1-C6Alkylaminocarbonyl, unsubstituted or substituted C1-C6Alkylamido, amido, unsubstituted or substituted C1-C6-alkylureido, substituted or unsubstituted C1-C6Alkyl carbamates, unsubstituted or substituted C1-C6Alkylamino, unsubstituted or substituted C1-C6Alkyl ammonium, unsubstituted or substituted C1-C6Alkylsulfonyloxy, unsubstituted or substituted C1-C6-alkylsulfonyl, unsubstituted or substituted C1-C6-alkylsulfinyl, unsubstituted or substituted C1-C6Alkyl sulfanyl, unsubstituted or substituted C1-C6-alkylsulfonylamino, unsubstituted or substituted C1-C6Alkylaminosulfonyl, hydroxy, halogen, cyano.
According to a preferred embodiment, R7Are substituents that include ionizable (especially protonatable) moieties.
In particular, R7Possibly selected from carboxyl or amino residues.
Or, R7Possibly selected from any of the above substituents bearing at least one carboxyl or amino group. The preferred ionizable (protonatable) residue is a cyclic tertiary amine (a heterocycloalkyl).
More preferably C1-C6Alkylamino, heterocycloalkyl, such as piperazine or piperidine, C1-C6Alkyl heterocycloalkyl, aminocarbonyl, C1-C6-alkylaminocarbonyl radical, C1-C6Alkyl amido radical, C1-C6-alkylsulfonyl, C1-C6-an alkylcarboxy group. Most preferred are dimethylaminomethyl, 2- (dimethylamino) ethyl, 1-methyl-3-piperidinyl, (4-acetyl 1-piperazinyl) methyl.
According to another particular embodiment, the substituent B is a 1, 3, 4-oxadiazole of general formula (IV) or a tautomer thereof of general formula (III):
x in the general formulae (III) and (IV) is O or S, but X may also be a bond in the general formula (IV). When X is O or S, and R8The compounds of formula IV correspond to tautomers of formula III for hydrogen.
R in the general formula (IV)8Selected from: hydrogen, unsubstituted or substituted C1-C6Alkyl, unsubstituted or substituted C2-C6-alkenyl, unsubstituted or substituted C2-C6-alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl, optionally containing at least one heteroatom (e.g. 1 to 3) selected from N, O, S, acyl residue, unsubstituted or substituted C1-C6Alkylaryl, unsubstituted or substituted C1-C6-alkylheteroaryl, unsubstituted or substituted C1-C6Alkenylaryl, unsubstituted or substituted C1-C6Alkenylheteroaryl, substituted or unsubstituted alkoxycarbonyl, carboxylic acid amide, substituted or unsubstituted C1-C6Alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, halogen, cyano, substituted or unsubstituted C1-C6-alkylcarbonyl, substituted or unsubstituted arylcarbonyl or heteroarylcarbonyl, substituted or unsubstituted saturated or unsaturated C4-C8Cycloalkylcarbonyl, wherein the cycloalkyl or aryl or heteroaryl substituent may be further fused with 1-2 cycloalkyl or aryl or heteroaryl groups, and wherein the alkyl, alkenyl, alkynyl chain may be interrupted by a heteroatom selected from N, O or S.
Especially more preferred pyrrolidine derivatives are those of general formula I, wherein a is- (C ═ O), R1Is C1-C6Alkyl radical, R2Is aryl or heteroaryl, each R3’R4’R5And R6Is hydrogen and B is an oxadiazole of the general formula IIa, IIb, III or IV.
The most preferred pyrrolidine derivatives are compounds of formula I, wherein a is- (C ═ O), R1Is methyl, R2Is (un) substituted aryl or (un) substituted heteroaryl, R3’R4’R5And R6Each is hydrogen and B is an oxadiazole of the general formulae IIa, IIb, III and IV, in particular a 1, 2, 4-oxadiazole of the general formulae IIa and IIb.
The most preferred pyrrolidine derivatives are compounds of formula I, wherein a is- (C ═ O), R1Is methyl, R2Is biphenyl, R3’R4’R5And R6Each is hydrogen and B is an oxadiazole of the general formulae IIa, IIb, III and IV, in particular a 1, 2, 4-oxadiazole of the general formulae IIa and IIb.
The compounds of formula I may contain one or more asymmetric centers and may therefore exist as enantiomers or diastereomers. It is to be understood that the present invention encompasses not only the individual isolated isomers or enantiomers of the compounds of formula I but also mixtures thereof. In a preferred embodiment, the pyrrolidine derivative of formula I obtained has an enantiomeric excess of at least 52% ee, preferably of at least 92-98% ee.
Specific examples of compounds of formula I include:
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- [ (2 '-methyl [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (1, 3, 4-oxadiazol-2-yl) -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (5-oxo-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (5-thio-4, 5-dihydro-1, 3, 4-oxadiazol-2-yl) -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -5- (3-benzyl-1, 2, 4-oxadiazol-5-yl) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (3- { [ (2-furylmethyl) sulfanyl ] -methyl } -1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ 2-oxo-2- (1-pyrrolidinyl) ethyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ (2-pyridylsulfanyl) methyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (4-fluorophenyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ (2-thiophenesulfanyl) methyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [2- (3, 5-dimethyl-1H-pyrazol-1-yl) ethyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ (methylsulfonyl) methyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (5-methyl-3-isoxazolyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (2-thienylmethyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -Biphenyl ] -4-ylcarbonyl) -5- (3-phenyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (3- { [ (2-furylmethyl) sulfonyl ] -methyl } -1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -5- [3- (aminomethyl) -1, 2, 4-oxadiazol-5-yl ] -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -Biphenyl ] -4-ylcarbonyl) -5- {3- [ (RS) -hydroxy (phenyl) methyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ (1RS) -1-hydroxypropyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (hydroxymethyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ (1S, 2R) -2-hydroxycyclohexyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- [ (1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-carboximidoyl
(3Z, 5RS) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (4-piperidinyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-carboximidoyl
(3EZ, B) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ (3RS) -piperidinyl ] -1, 2, 4-oxadiazol-5-yl } 3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1-Biphenyl ] -4-ylcarbonyl) -5- {3- [ (2RS) -piperidinyl ] -1, 2, 4-oxadiazol-5-yl } 3-pyrrolidinone O-carboxim-ine
(3EZ, 5S) -1- [ (2 '-chloro [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methoxime
(3EZ, 5S) -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -1- { [2 '- (trifluoromethyl) [1, 1' -biphenyl ] -4-yl ] -carbonyl } -3-pyrrolidinone O-methoxime
(3Z, 5S) - [ (2 '-fluoro [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- [ (4 '-fluoro [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (1, 2, 4-oxadiazol-3-yl) -3-pyrrolidinone O-carboximidoyl
(3E, 5S) -1- [ (2 '-fluoro [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl
(3E, 5S) -1- [ (2 '-methyl [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl
(3Z, 5S) -1- [ (2 '-methyl [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (phenoxymethyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -Biphenyl ] -4-ylcarbonyl) -5- (5-phenyl-1, 2, 4-oxadiazol-3-yl) -3-pyrrolidinone O-carboximidoyl
N- ({3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } methyl) acetamide
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [4- (hydroxymethyl) phenyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methyloxime-1, 2, 4-oxa
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (2-hydroxyethyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (2S) -2-hydroxy-2-phenylethyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methyloxime
{3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } methylformamide
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (methoxymethyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (2-phenoxymethyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (2-methoxyethyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -5- [5- (1-acetyl-4-piperidinyl) -1, 2, 4-oxadiazol-3-yl ] -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (2-pyridyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -Biphenyl ] 4-ylcarbonyl) -5- [5- (3-thienyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (5-ethyl-1, 2, 4-oxadiazol-3-yl) -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (5-cyclopentyl-1, 2, 4-oxadiazol-3-yl) -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -Biphenyl ] -4-ylcarbonyl) -5- {5- [ (RS) -hydroxy (phenyl) methyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (1RS) -1-hydroxy-2-phenylethyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (1R) -1- (dimethylamino) -2-phenylethyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (3-pyridyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (4-pyridyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl
(3Z, 5) -5- {5- [ (4-acetyl-1-piperazinyl) methyl ] -1, 2, 4-oxadiazol-3-yl } -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -5- [3- (1-acetyl-4-piperidinyl) -1, 2, 4-oxadiazol-5-yl ] -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-methoxime
(3EZ, 5S) -5- {5- [ (4-acetyl-1-piperazinyl) methyl ] -1, 2, 4-oxadiazol-3-yl } -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime
N- ({3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } methyl) -3- (1-piperidinyl) propanamide
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (3S) -1-methylpiperidinyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (3R) -1-methylpiperidinyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (6-hydroxy-3-pyridinyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-methyloxime
(3Z, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (dimethylamino) methyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methoxime
(3EZ, 5S) -5- {5- [ (1S, 2R) -1-amino-2-hydroxypropyl ] -1, 2, 4-oxadiazol-3-yl } -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (3S) -piperidinyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (3R) -piperidinyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-carboximidoyl
(3EZ, 5RS) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (1-methyl-3-piperidinyl) -1, 2, 4-oxadiazol 3-yl ] -3-pyrrolidinone O-carboximidoyl
(3R) -3- {3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } -1-piperidinecarboxylic acid tert-butyl ester
4- ({3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } methyl) -2, 6-piperazinedione
(3Z, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-carboximidoyl
(3Z, 5S) -1- [ (2 ' -chloro-4 ' -fluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (1-methyl-4-piperidinyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (dimethylamino) methyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (1-methyl-4-piperidinyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-methoxime
(3EZ, 5S) -5- {5- [ (1S) -1-amino-2-hydroxyethyl ] -1, 2, 4-oxadiazol-3-yl } -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime
5- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -N- [3- (dimethylamino) propyl ] -1, 2, 4-oxadiazole-3-carboxamide
(3E, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (dimethylamino) methyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methoxime
(3S) -3- {3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } -1-piperidinecarboxylic acid tert-butyl ester
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (4-methyl-1-piperazinyl) methyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methoxime
(3Z, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (4-methyl-1-piperazinyl) methyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methoxime
5- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazole-3-carboxylic acid ethyl ester
(3E, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-carboximidoyl
N- ({3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } methyl) -3- (dimethylamino) propanamide
4- (2- {3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) -pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } ethyl) -1-piperazinecarboxylic acid tert-butyl ester
(3EZ, 5S) -1- [ (2 ' -chloro-4 ' -fluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- [3- (2-hydroxyethyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- [ (4 ' -fluoro-2 ' -methyl [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [2- (dimethylamino) ethyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methoxime
2- {5- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-3-yl } ethyl [ (tert-butoxycarbonyl) amino ] -acetate
N- ({3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } methyl) -2- (dimethylamino) acetamide
(3EZ, 5S) -1- [ (2 ' -chloro-4 ' -fluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methoxime
(3EZ, 5S) -5- {5- [ (1S) -1-amino-2-tert-butoxyethyl ] -1, 2, 4-oxadiazol-3-yl } -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime
4- {5- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-3-yl } -1-piperidinecarboxylic acid tert-butyl ester
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (1-piperazinylmethy l) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl
(4S) -4- {3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } -4- [ (tert-butoxycarbonyl) amino ] -butyric acid tert-butyl ester
4- { [ (2S, 4EZ) -2- (5- { [ (tert-butoxycarbonyl) amino ] -methyl } -1, 2, 4-oxadiazol-3-yl) -4- (methoxyimino) pyrrolidinyl ] -carbonyl } -1, 1' -biphenyl
2- {3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-yl-carbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } ethylcarbamic acid tert-butyl ester
2- {5- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-3-yl } ethylamino acetate
(3E, 5S) -1- [ (2 ', 4 ' -difluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- [ (2 ', 4 ' -difluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime
4- { [ (2S, 4EZ) -2- (5- { (1S) -2-tert-butoxy-1- [ (tert-butoxycarbonyl) amino ] -ethyl } -1, 2, 4-oxadiazol-3-yl) -4- (methoxyimino) pyrrolidinyl ] -carbonyl } -1, 1' -biphenyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (5-vinyl-1, 2, 4-oxadiazol-3-yl) -3-pyrrolidinone O-methyloxime
4- { [ (2S, 4EZ) -2- (5- { (1S, 2R) -2-tert-butoxy-1- [ (tert-butoxycarbonyl) amino ] -propyl } -1, 2, 4-oxadiazol-3-yl) -4- (methoxyimino) pyrrolidinyl ] -carbonyl } -1, 1' -biphenylyl
(3Z, 5S) -1- [ (2 ', 4 ' -difluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime
4- ({3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } methyl) -1-piperazinecarboxylic acid tert-butyl ester
A further aspect of the present invention relates to the use of pyrrolidine oxadiazole or thiadiazole derivatives of general formula I as medicaments, in particular for the treatment and/or prevention of abortion, premature birth, pre-dissection cessation of labour and caesarean section. Preferred compounds of the general formula I are those which modulate OT function and can therefore be used, inter alia, for the treatment and/or prophylaxis of disorders which are mediated via the oxytocin receptor. The treatment comprises modulating, in particular down-regulating or antagonizing, the oxytocin receptor.
More particularly, the compounds of the invention are useful in the treatment of miscarriage, dysmenorrhea and in stopping labor prior to caesarean delivery.
A further object of the present invention is furthermore a process for the preparation of pyrrolidine derivatives of the general formula I.
Exemplary pyrrolidine derivatives of the invention are prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions are given (e.g. reaction temperature, time, moles of reagents, solvents etc.), other experimental conditions may be used unless otherwise indicated. The optimum reaction conditions may vary depending on the reactants or solvents used, but can be determined by routine optimization by one skilled in the art.
Generally, pyrrolidine derivatives of general formula I can be obtained by liquid and solid phase chemistry schemes, if anhydrous.
According to one method, pyrrolidine derivatives of the general formula I, wherein the substituent B is a 1, 2, 4-oxadiazole of the general formula (IIa), can be prepared by reacting the corresponding carboxylic acid compound V with an amidoxime VI, wherein the substituent R is1-R7And a is as defined above, prepared via a known liquid phase chemistry scheme as described in that example and scheme 1 below.
Scheme 1
Amidoxime component VI is either commercially available or can be prepared by one skilled in the art from the corresponding nitrile VII and hydroxylamine under standard atmospheric conditions according to the methods shown in the examples and scheme 2.
Flow chart 2
Nitrile component VII is commercially available or a carboxylic acid is converted to the corresponding nitrile VII by functional group conversion methods well known to those skilled in the art starting from a carboxylic acid VIII, such as shown in scheme 3. Examples include (i) reduction of carboxylic acid VIII to the corresponding aldehyde (carbaldehyde) followed by conversion to the corresponding oxime and dehydration of the latter using, for example, N' -dicarbonylimidazole or similar reagents to yield the corresponding nitrile VII, or (ii) conversion of carboxylic acid VII to the corresponding primary carboxamide followed by dehydration using standard conditions well known to those skilled in the art to yield the corresponding nitrile IV, as described in the examples below.
Flow chart 3
Pyrrolidine-2-carboxylic acid V (see scheme 1), wherein the substituent R1-R7And a is as defined above, can be prepared from a compound of formula IX and substituted hydroxylamine X by reaction using standard synthetic methods as described in the examples below and scheme 4.
Flow chart 4
Compounds of general formula X are commercially available or prepared from N-Boc-hydroxylamine XI and alkylating agent XII (X ═ Cl, Br, I) by standard synthetic methods as depicted in scheme 5 and in the examples below.
Flow chart 5
Ketone compounds of the general formula IX, in which the substituents R1-R7And A is as defined above, can be prepared by oxidation of a commercially available suitable nitrogen protected 4-hydroxyproline XIII using standard synthetic methods as described in the examples and scheme 6 below. Alternatively, the compounds of formula IX may be obtained by converting the oxime ethers of the compounds of formula V to the ketone residue, for example under mild hydrolysis conditions as described below and in the examples. If, in this case, the ketone compound IX is successively recontacted with the different hydroxylamine components X, as shown in scheme 6, the overall conversion V → IX → V corresponds to R in the oxime ether residue of the formula V1The exchange of (2). Similar oxime ether interconversion is possible as shown in scheme 6 for the transformation of compounds of general formula I (I → XIV → I).
Flow chart 6
According to another method, known liquid phase chemical schemes such as those shown in the examples and in scheme 7, can be prepared by reacting the corresponding amidoxime acid compound XV, wherein the substituent R is1-R7And A is as defined above, with a carboxylic acid VIII to prepare pyrrolidine derivatives of formula ICompound (lib) wherein substituent B is a 1, 2, 4-oxadiazole of formula (IIb).
Flow chart 7
By the corresponding nitrile XVI, in which the substituents R1-R7And A is as defined above, with hydroxylamine under standard conditions known to those skilled in the art, such as those shown in the examples and scheme 8, to produce the amidoxime component XV. The nitrile component XVI itself can be prepared, for example, from the corresponding carboxylic acid, in which the substituents R are present, by functional group interchange processes known to those skilled in the art for converting carboxylic acids to the corresponding nitriles1-R7And A is as defined above. Examples include: (i) reduction of the carboxylic acid V to the corresponding aldehyde followed by its conversion to the corresponding oxime, which is then converted to the corresponding nitrile XVI by dehydration using, for example, N' -carbonyldiimidazole or similar reagents; or (ii) conversion of the carboxylic acid V to the corresponding primary amide, which is subsequently dehydrated to the corresponding nitrile XVI using standard conditions well known to those skilled in the art, such as described in the examples below
Flow chart 8
By the corresponding hydrazide compounds XVII, where the substituents R1-R7And A is as defined above, by a liquid phase chemical scheme, in a manner known to those skilled in the art, such as in the examples and scheme 9 below, to provide pyrrolidine derivatives of general formula I wherein substituent B is a 1, 3, 4-oxadiazole of general formula III and/or IV. For example, compounds of formula I wherein the substituent B is a 1, 3, 4-oxadiazole of formula III may be prepared by reaction of XVII with CDI or CS2 under basic conditionsX in the obtained product is O or S respectively. Or hydrazide intermediate XVII with TMOF and then with P under toluene reflux2O5Reacting to obtain the compound shown in the general formula I, wherein B is IV.
Flow chart 9
Hydrazide compounds XVII are prepared by, for example, reacting the corresponding carboxylic acids V, wherein the substituents R are as shown in the examples and scheme 10, under standard conditions known to those skilled in the art1-R7And A is as defined above, via the corresponding methyl ester XVIII and subsequent reaction with hydrazine.
Flow chart 10
The compounds of the formula I are thus obtained from precursors of the formula V/XVIII (cf. scheme 1, 7-10 above), in which the substituent R is1-R8And A is as defined above. Typically, the precursor of formula V/XVIII initially contains a protecting group on the pyrrolidine ring nitrogen atom, e.g., Boc, Fmoc, or others, so that V 'and/or XVIII' (-A-R)2Protecting group, PG) as shown in scheme 11. For the synthesis of the final compounds I, by appropriate nitrogen-substituents, e.g. acyl substituents, -C (O) -R2or-SO2-R2Substituents, for example, treatment with an acylating or sulfonating agent XX typically deprotect and replace the N protecting group of V 'and/or XVIII'. The compounds of the general formula (XX) may also be carboxylating agents, sulfonating agents, iminating agents, amidating agents, thioamidating agents, or alkylating agents. As shown in scheme 11 (A or B, respectively) and the examples, the formation of the oxadiazole, or thiadiazole ring can be preceded or precededThereafter, the desired residue (-A-R) is substituted2) Attached to the nitrogen atom of the pyrrolidine. The choice of the best synthetic sequence depends on the substituent R1-R8Of (in particular the substituent R)7). The preferred acylating reagent XX is an acid chloride (XXa), and the ligation is usually carried out using a suitable tertiary amine base or carboxylic acid (XXb), and a peptide coupling reagent such as DIC or EDC.
A compound of the general formula I, wherein A is- (C ═ O) -O-, -SO-2-，-SO2NH-，-C(＝NH)-，-(C＝O)-NH，-(C＝S)-NH，-CH2Possibly substituted by corresponding carboxylating, sulfonating, sulfamiding, imidizing, amidating, sulfamiding, or alkylating agents, such as sulfonyl chlorides, isocyanates, isothiocyanates, chloroformates, substituted haloalkanes, or other compounds capable of yielding sulfonamides, ureas, thioureas, carbamates, substituted alkyl derivatives, and the like, respectively.
Flow chart 11
According to a further general method, a compound of formula I can be converted to another compound of formula I' by appropriate protection/deprotection/functional group interconversion procedures known to those skilled in the art, as illustrated in the examples below and scheme 12.
Flow chart 12
Examples include:
according to another method, pyrrolidine derivatives of general formula I can be prepared by a novel solid phase process as depicted in scheme 13 and the examples below. For example, solid phase synthesis of compounds of general structure I of B ═ IIa, N-Boc protected pyrrolidine derivative V is reacted with a resin containing a nucleophile cleavable linker, such as Kaiser oxime resin, under standard carbodiimide-mediated coupling conditions known to those skilled in the art. BF3 OEt diluted with TFA/DCM, HOAc/DCM2Deprotection affords compounds of formula XXIV. The latter are treated with acylating agents of the formula XX, where the substituents A and R2As defined above, and LG is a suitable leaving group. Preferred acylating agents XX are acid chlorides (XXa) linked using tertiary amine bases or carboxylic acids (XXb) linked using coupling reagents such as DIC, EDC, TBTU, DECP or other peptides to give compounds of formula XXIII. Compounds of formula I, wherein A is different from the carbonyl function, can be prepared by displacement of compounds of formula XX with compounds containing suitable functional groups, such as sulfonyl chlorides, isocyanates, isothiocyanates, chloroformates, substituted haloalkanes, etc., to give sulfonamide ureas, thiourea carbamates, substituted alkyl derivatives, etc., respectively. To finally obtain the compounds of general formula I, the resin linkage is cleaved by prolonged reaction with amidoxime VI, followed by heating using, for example, pyridine. The circles in scheme 13 represent the resin beads to which the corresponding compounds are attached during solid phase synthesis. Other derivatives of general formula I can be prepared by known modifications or alterations to the process of scheme 13. Furthermore, the above Kaiser oxime resins, other suitable reagents, in particular resins, are well known to those skilled in the art for carrying out solid phase synthesis of compounds of formula I.
Flow chart 13
If pure optically pure starting materials are used, the reactions of the above schemes in turn lead to optically pure compounds of the formula I. Depending on the commercially available starting materials of the formulae V-VIII, X and/or XX used in the (R) -or (S) -form, the enantiomers of (R) -or (S) -can be obtained.
However, the reaction processes given in the above schemes generally give mixtures of (E) -and (Z) -isomers of exocyclic double bond substituents of the pyrrolidine ring. In all cases of investigation, the (E)/(Z) -isomer may be isolated by chromatographic methods well known to those skilled in the art, such as reverse phase High Pressure Liquid Chromatography (HPLC) or silica gel Flash Chromatography (FC), or may be enriched continuously by selective crystallization in a suitable solvent or solvent mixture. The absolute configuration of the exocyclic double bond is determined by NMR techniques well known to those skilled in the art (e.g., assignment of the configuration of the oxime function, see, e.g., E.Breitmaier, W.Voelter Carbon-13 NMRSpecroscopy, 3. frdVCH, 1987, p.240). To increase the overall yield of the preferred isomer (typically the (Z) -isomer), the less preferred isomer (typically the (E) isomer) can be recovered by evaluating the re-isomerization in an organic solvent containing trace amounts of an acid, such as HCl, followed by another (E)/(Z) separation by chromatographic or crystallization methods as shown in scheme 14.
Flow chart 14
If the general synthetic methods described above are not suitable for obtaining compounds of the general formula I and/or intermediates necessary for the synthesis of the compounds I, suitable preparation methods well known to the person skilled in the art should be used. In general, the synthetic route for any compound of formula I depends on the particular substituents per molecule, as well as the ready availability of the necessary intermediates. These factors are also understood by those skilled in the art. All protection and deprotection methods are described in PhilipJ.Kocienski, "protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and "Protective Groups in organic Synthesis", Wiley-Interscience, 1991, by Theodera W.Greene and Peter G.M.Wuts.
The compounds of the invention may be isolated from the associated solvent molecules by evaporative crystallization from a suitable solvent. Pharmaceutically acceptable acid addition salts of the compounds of formula I, which contain a basic center, can be prepared by conventional methods. For example, one method is to treat the free base with a suitable acid (either as it is or in a suitable solution) and then isolate the salt by filtration or evaporation of the reaction solvent under vacuum. Pharmaceutically acceptable base addition salts thereof may be obtained in an analogous manner by reacting a solution of the compound of formula I with a suitable base. Both types of salts can be formed or interconverted using ion exchange resin techniques.
A final aspect of the present invention relates to the use of compounds of general formula I for the treatment of preterm labor, premature birth, dysmenorrhea, preferably the use of compounds of general formula (I) for modulating oxytocin receptors, for the preparation of pharmaceutical compositions for modulating oxytocin receptors and formulations comprising an active compound of general formula (I). Such receptors that modulate oxytocin are considered suitable routes for the treatment of abortion, premature birth and dysmenorrhea. Accordingly, pharmaceutical compositions comprising a compound of formula I in combination with a pharmaceutically acceptable carrier, diluent or excipient are also within the scope of the present invention. Such carrier, diluent or excipient compounds suitable for the preparation of pharmaceutical compositions are known to those skilled in the art. Furthermore, the present invention provides a compound for use as a medicament.
The compounds of the present invention may be incorporated in pharmaceutical compositions and unit dosage forms together with conventional additives, carriers, diluents or excipients, and these forms may be solids such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs or capsules filled with them, all of which may be administered orally or parenterally (including subcutaneous injections) in sterile form. All pharmaceutical compositions and unit dosage forms may contain the ingredients in the usual proportions, with or without additional active ingredients or main ingredients, and such unit dosage forms may contain suitable effective amounts of the active ingredients commensurate with the intended daily amount.
When used as a medicament, the pyrrolidine derivatives of the present invention are usually administered in the form of a pharmaceutical composition. These compositions may be prepared in conventional pharmaceutical techniques and comprise at least one active compound. Typically, the compounds of the present invention are administered in a pharmaceutically effective amount. The amount of the compound actually used will usually be determined by a physician, and will depend on the relevant circumstances, including the condition to be treated, the chosen route of administration, the compound actually administered, the age, weight, response of the individual patient, and the severity of the symptoms.
The pharmaceutical compositions of the present invention may be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal routes. Oral compositions may take the form of liquid solutions or suspensions and loose powders. More commonly, however, pharmaceutical compositions are administered in unit dosage form for convenient and accurate metering. The term "unit dosage form" refers to discrete units suitable as unitary dosages for humans or other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, pre-filled ampoules or pre-measured ampoules of liquid composition or pellets, capsules or the like of solid composition. In these compositions, the pyrrolidine oxadiazole compound is typically a minor component (about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight) in combination with the remainder of the various excipients or carriers and processing aids to form the desired dosage form.
Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous vehicles with buffers, suspending agents, and dispersing agents, coloring agents, flavoring agents, and the like. Solid forms may include, for example, any of the following ingredients, or compounds of similar nature: binders such as microcrystalline cellulose, gum tragacanth or gum; excipients such as starch or lactose; disintegrating agents such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
Injectable compositions are typically prepared using injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art as substrates. As mentioned above, the pyrrolidine derivative of formula I is generally a minor component, usually 0.05 to 10% by weight, with the remainder being an injectable carrier or the like. .
The above components for oral compositions or injectable compositions are illustrative only. Further materials and processing techniques, etc. such as Remington's Pharmaceutical Sciences, 17thEdition, 1985, Marckpublishing Company, Easton, Pennsylvania, section VIII, which is incorporated herein by reference.
The compounds of the present invention may also be administered in a sustained release form or from a sustained release drug delivery system. Representative sustained release materials may also be found included in the materials described by Remington's Pharmaceutical Sciences.
The present invention is illustrated below by some examples, which should not be construed as limiting the scope of the invention. The HPLC, NMR and MS data provided in the example below were obtained by the following methods.
The following abbreviations are used in the examples: min (min), hr (h), g (g), mmol (mmol), m.p. (melting point), eq (equivalent), mL (mL), μ l (μ l), mL (mL), ACN (acetonitrile), Boc (butoxycarbonyl), CDCl (acetonitrile), Boc (butyloxycarbonyl), n (t-butyl-n-ethyl-n-butyl-n-ethyl3(deuterated chloroform), CDI (carbonyldiimidazole), cHex (cyclohexane), DCM (dichloromethane), DECP (diethylcyanophosphate), DIC (diisopropylcarbodiimide), DMAP (4-dimethylaminopyridine) DMF (dimethylformamide), DMSO (dimethyl sulfoxide), DMSO-d6(deuterated dimethyl sulfoxide), EDC (1- (3-dimethyl-amino-propyl) -3-ethylcarbodiimide), EtOAc (ethyl acetate), Et2O (diethyl ether), Fmoc (9-fluorenylmethoxycarbonyl), HOBt (1-hydroxybenzotriazole), Kaiser oxime resin (4-nitrobenzone oxime resin))；K2CO3(Potassium carbonate), NaH (sodium hydride), NaHCO3(sodium bicarbonate), N-BuLi (N-butyllithium), TBTU (O-benzotriazolyl-N, N, N ', N' -tetramethyluronium tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TMOF (trimethyl orthoformate), MgSO4(magnesium sulfate), PetEther (petroleum ether), rt (room temperature).
Examples
Intermediate 1: (2S) -1- (tert-Butoxycarbonyl) -4-oxo-2-pyrrolidinecarboxylic acid (see scheme 6, Compound XIII)
Commercially available (2S, 4R) -1- (tert-butoxycarbonyl) -4-hydroxy-2-pyrrolidinecarboxylic acid (30g, 0.13mol) was dissolved in acetone (1500 ml). A mechanical stirrer was placed in the flask and the solution was stirred vigorously. Chromium trioxide (66.7g, 0.667mol) was dissolved in water (40ml), concentrated sulfuric acid (53.3ml) was then added, and sufficient water was added to bring the solution volume to 115ml to prepare an 8N chromic acid solution, which was newly prepared 8N chromic acid solution (115ml) was added dropwise over 30 minutes with continuous vigorous stirring, maintaining the optimum temperature at 25 ℃ (reaction exotherm) with an ice bath. After the chromic acid solution was completely added, the optimal temperature was maintained at 25 ℃ and stirring was continued for another 15 minutes. Methanol (20mL) was added to the reaction mixture to stop the reaction. The reaction was controlled for exotherm by using an ice bath and adding a small amount of crushed ice directly to the reaction mixture itself if necessary. The reaction mixture was filtered using a pad of celite and then concentrated in vacuo. The resulting acidic solution was extracted with ethyl acetate (3x300ml) and the combined organic layers were washed with brine (2x100 ml). The organics were then dried over magnesium sulfate and concentrated in vacuo. Recrystallization of the crude product from ethyl acetate gave the product as a white crystal, (2S) -1- (tert-butoxycarbonyl) -4-oxo-2-pyrrolidinecarboxylic acid (22.55g, 76%). The enantiomeric intermediate, (2R) -1- (tert-butoxycarbonyl) -4-oxo-2-pyrrolidinecarboxylic acid was prepared by the same method starting from commercially available (2R, 4S) -1- (tert-butoxycarbonyl) -4-hydroxy-2-pyrrolidinecarboxylic acid.
1H NMR(360MHz，CDCl3)；1.4(m，9H)，2.5-3.0(m，2H)，3.7-3.9(m，2H)，4.75(dd，1H)
Intermediate 2: (2S, 4EZ) -1- (tert-Butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (see scheme 4, Compound V)
A solution of (2S) -1- (tert-butoxycarbonyl) -4-oxo-2-pyrrolidine-carboxylic acid (intermediate 1, 5.0g, 21mmol) and O-methylhydroxylamine hydrochloride (2.7g, 32.8mmol) in chloroform (100ml), triethylamine (5.5g, 55mmol) was prepared. The reaction mixture was stirred at room temperature overnight before removing the solvent. The resulting crude reaction mixture was dissolved in ethyl acetate (150ml) and washed rapidly with 1N HCl (40 ml). The acid layer was extracted with ethyl acetate (3x20ml), the combined organic layers were washed with brine, filtered and the solvent removed in vacuo before drying over magnesium sulfate. The title product was isolated as a pale yellow oil (5.3g, 94%)
1H NMR(400MHz，CDCl3)；1.45(m，9H)，2.8-3.2(m，2H)，3.9(s，3H)，4.2(m，2H)，4.5-4.7(m，1H)。
Intermediate 3: (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (ethoxyimino) -2-pyrrolidinecarboxylic acid (see scheme 4, Compound V)
A1: 1(100ml) solution of a mixture of (2S) -1- (tert-butoxycarbonyl) -4-oxo-2-pyrrolidinecarboxylic acid (intermediate 1, 5.0g, 22mmol) and O-ethylhydroxylamine hydrochloride (6.4g, 65.5mmol) in pyridine/ethanol was prepared. The reaction mixture was heated to reflux for 2.5 hours before cooling to remove the solvent. The residue was dissolved in ethyl acetate and washed rapidly with 1.3N HCl (40 ml). The acid layer was extracted with ethyl acetate (3 × 20ml), the combined organic layers were washed with brine before drying over magnesium sulfate, filtered and the solvent removed in vacuo to isolate the desired product as a pale yellow oil (5.5g, 93%).
1H NMR(400MHz，DMSO)；1.3(t，3H)，1.55(m，9H)，2.9-2.7(m，1H)，3.4-3.1(m，1H)，4.1-4.3(m，4H)，4.6(m，1H)，12-13.5(br，1H)。
Intermediate 4: (2S, 4EZ) -4- [ (allyloxy) imino ] -1- (tert-butoxycarbonyl) -2-pyrrolidinecarboxylic acid (see scheme 4, Compound V)
A solution was prepared containing a 1: 1(100ml) mixture of (2S) -1- (tert-butoxycarbonyl) -4-oxo-2-pyrrolidinecarboxylic acid (intermediate 1, 5.0g, 22mmol) and O-allylhydroxylamine hydrochloride monohydrate (7.2g, 65.5mmol) in pyridine/ethanol. The reaction mixture was heated to reflux for 2.5 hours before cooling to remove the solvent. The resulting residue was dissolved in ethyl acetate and washed rapidly with 1.3N HCl (40 ml). The acid layer was extracted with ethyl acetate (3 × 20ml), the combined organic layers were washed with brine before drying over magnesium sulfate, filtered and the solvent removed in vacuo to isolate the desired product as a pale yellow oil ((5.9g, 94%).
1H NMR(400MHz，CDCl3) (ii) a 1.5(m, 9H), 2.8-3.2(m, 2H), 4.2(m, 2H), 4.5-4.7(m, 3H), 5.25(m, 2H), 5.9(m, 1H), 11.1 (broad singlet, 1H).
Intermediate 5: (2S.4EZ) -1- (tert-butoxycarbonyl) -4- { [ (4-methoxybenzyl) oxy ] -imino } -2-pyrrolidine-carboxylic acid (see scheme 4, Compound V)
The title compound was obtained in 85% yield as a gum using the same procedure as for the preparation of intermediate 2, but starting from (2S) -1- (tert-butoxycarbonyl) -4-oxo-2-pyrrolidinecarboxylic acid (intermediate 1) and 1- [ (aminooxy) methyl ] -4-methoxybenzene (intermediate 6).
1H NMR(400MHz，DMSO)；1.5(m，9H)，2.7-2.9(m，1H)，3.9(s，3H)，4.2(m，3H)，4.6(m，1H)，5.15(s，2H)，7.1(d，2H)，7.45(d，2H)。
Intermediate 6: 1- [ (Aminooxy) methyl ] -4-methoxybenzene (see scheme 5, Compound X)
A solution of N-Boc-hydroxylamine (2.0g, 17.1mmol) in dry THF (60ml) was prepared. Sodium hydride (1.1g of a 60% suspension in paraffin oil, 25.7mmol) was then added and the suspension stirred, with catalytic amounts of KI added before 4-methoxybenzyl chloride (3.2g, 20.4mmol) was carefully added. The reaction was stirred overnight and then the solvent was removed in vacuo. The residue was extracted with diethyl ether (100ml) and bubbled with HCl for 20 minutes, and the product started to precipitate. The reaction was stopped and allowed to stand overnight. Filtration gave an off-white waxy product (39-52% yield based on the reaction batch).
1H NMR(400MHz，D2O)；3.8(s，3H)，5(s，2H)，7.0(d，2H)，7.4(d，2H)。
Intermediate 7: non-commercial amidoximes
The method A comprises the following steps: for example N' -hydroxyethylimide amide (acetamidoxime)
(see scheme 2, Compound VI)
45ml of high purity acetonitrile was added to 90ml of 50% hydroxylamine/50% water (w/w) and stirred in a magnetic stirrer at 25 ℃. Most often, crystalline N' -hydroxyethyliminamide is isolated. The mixture was stirred at room temperature for 24 hours until crystals were completely formed, and then the crystals were filtered the next day. In the case where no solid initially separates out, a small amount of the solution may be first removed and evaporated, and the crystals formed may then be used as seeds for a large amount of the solution. The product was purified as follows: the crystals were filtered and then dissolved in a nonpolar solvent (perfluorohexane) with heating and recrystallized by cooling at room temperature overnight. The crystalline material was then filtered and washed with perfluorohexane. The target product, N' -hydroxyethylimino amide, has a melting point of 136-138 ℃ and a yield of about 56%.
The method B comprises the following steps: for example tert-butyl 2-amino-2- (hydroxyimino) ethylcarbamate (scheme 2, Compound XI)
Triethylamine (535. mu.l, 3.84mmol) was added to a solution of cyanomethylcarbamic acid tert-butyl ester (500mg, 3.20mmol) and hydroxylamine hydrochloride (227mg, 3.84mmol) in ethanol (10 ml). The reaction mixture was heated at 80 ℃ overnight. The resulting solution was then evaporated in vacuo. To the residue was added ethyl acetate (10ml) and then filtered to remove triethylamine hydrochloride, followed by evaporation in vacuo to give the crude product.
1H NMR(360MHz，DMSO)：1.53(s，9H)，3.62-3.63(d，2H)，5.33-5.44(s，2H)，7.10(t，1H)，8.94(s，1H)。
Similarly, using method B, and starting with the appropriate commercially available nitrile and hydroxylamine hydrochloride, the following guanamidoxime intermediate was obtained: (2RS) -N ', 2-Dihydroxybutaneimide amide, (1S, 2R) -N', 2-bishydroxycyclohexanecarbonimide amide, N ', 3-dihydroxypropaneimide amide, N, 2-dihydroxyethylenimide amide, (2RS) -N', 2-bishydroxy-2-phenylethaneimide amide, tert-butyl 4- [ amino (hydroxyimino) methyl ] -1-piperidinecarboxylate, (3RS) -tert-butyl 3- [ amino (hydroxyimino) methyl ] -1-piperidine-carboxylate, (2RS) -tert-butyl 2- [ amino (hydroxyimino) methyl ] -1-piperidinecarboxylate, ethyl amino (hydroxyimino) acetate.
Intermediate 8: (2S, 4EZ) -1- ([1, 1 '-Biphenyl ] -4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2 pyrrolidinemethaneiminamide (scheme 8, Compound XV)
1- (tert-Butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2, 95.9g, 0.371mol) was placed in a 3L flanged flask equipped with an overhead stirrer, nitrogen inlet/outlet and temperature probe. Anhydrous THF (1.15L) was then added to the flask, and the solution was cooled to-20 ℃ before triethylamine (52mL, 0.371mol) was added, and the solution was stirred for 10 minutes. Ethyl chloroformate (35ml, 0.371mol) was added to the solution over 10 minutes, maintaining the temperature at about-20 ℃. The reaction was stirred at this temperature for a further 30 minutes. A saturated THF solution of ammonia was prepared by blowing ammonia gas into 250mL of anhydrous THF solution at-78 deg.C for 15 minutes. The ammonia solution was added to the reaction flask over 10 minutes via cannula and the reaction temperature was maintained below-25 ℃ to control the exotherm. The solution was allowed to reach room temperature for more than 2 hours and then stirred for an additional hour. The reaction solvent was removed in vacuo and the residue partitioned between dichloromethane (500mL) and water (500 mL). After separation, the organic layer was washed with 3 × 250mL water, then the combined aqueous layers were washed with 2 × 250mL DCM, and then the DCM was washed again with 100ml of water. The combined organic layers were then dried over sodium sulfate, filtered and the solvent removed in vacuo. The desired product, tert-butyl (2S, 4EZ) -2- (aminocarbonyl) -4- (methoxyimino) -1-pyrrolidinecarboxylate, was obtained as a white amorphous solid (85.8g, 90%).
1H NMR(400MHz，DMSO)；1.5(s，9H)，2.65(m，1H)，3.15(m，1H)，3.9(s，3H)，4.2(m，2H)，4.5(m，1H)，7.2(m，1H)，7.65(m，1H)。
Tert-butyl (2S, 4EZ) -2- (aminocarbonyl) -4- (methoxyimino) -1-pyrrolidinecarboxylate (20g, 77.7mmol) was placed in a 1L round bottom flask under an inert atmosphere. The flask was then charged with anhydrous dichloromethane (140mL), followed by TFA (60 mL). The reaction was stirred at room temperature for 90 min and the disappearance of the starting material was monitored using Thin Layer Chromatography (TLC) (10% MeOH in DCM). Toluene (200mL) was then added to the reaction mixture and the solvent was removed in vacuo. The residue was redissolved in DCM (200mL), cooled to-5 ℃ and triethylamine (43mL, 311mmol) was added (exotherm). [1, 1' -Biphenyl ] -4-carbonyl chloride (16.8g, 77.7mmol) was added to the reaction mixture and stirred at room temperature for 1.5 hours. At this time, DCM (500mL) and 1M HCl (250mL) were added, the mixture was stirred vigorously and the precipitate was separated. The filtrate layer was separated and the organic layer was washed with HCl (250mL) and saturated bicarbonate (250 mL). The organic layer was then washed with DCM (250mL), the combined organics dried over magnesium sulfate, filtered, and concentrated to about 200mL at room temperature. The resulting slurry was dried to give the desired product (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxamide as a white solid (7.3g, 28%). A large amount of less pure material (7.9g, 30%) was obtained by adding hexane (125mL) to the filtrate.
1H NMR(400MHz，DMSO)；2.6(m，1H)，3.2(m，1H)，3.8(m，3H)，4.1-4.5(m，2H)，4.9(m，1H)，7.2-8.0(m，11H)。
(2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxamide (7.46g, 22.1mmol) was placed in a round bottom flask and pyridine (400mL) and p-toluenesulfonyl chloride (4.21g, 22.1mmol) were added. The resulting suspension was heated to 80 ℃ for 4 hours. The solvent was removed in vacuo and the residue was dissolved in DCM (400mL), which was washed with 1MHC1(2x75mL) and saturated bicarbonate (70mL) before drying the solution over magnesium sulfate, then filtered and the solvent removed, purified using short column silica gel chromatography, eluting initially with dichloromethane to remove low polar components followed by 1% MEOH in DCM to give the title compound, (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) 2-pyrrolidinenitrile (4.2g, 60%) as an off white solid.
1H NMR(400MHz，DMSO)；3.0(m，1H)，3.2(m，1H)，3.7(m，3H)，4.2(m，1H)，4.5(m，1H)，5.4(m，1H)，7.4-7.8(m，9H)。
According to the general procedure for the synthesis of intermediate 8 described above, triethylamine (1.94ml, 13.94mmol) was added slowly with stirring to a suspension of (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) -2-pyrrolidinecarbonitrile (3.71g, 11.62mmol) and hydroxylamine hydrochloride (0.97g, 13.94mmol) in ethanol (150 ml). The reaction mixture was then stirred at 80 ℃ for 16 hours and then cooled to room temperature. The solvent was removed by evaporation and the solid was suspended in water (100ML) and filtered. The solid was washed with diethyl ether (2x100ml) while the sinter was still dried under vacuum at 40 ℃ to give the desired product, (2S, 4EZ) -1- ([1, 1 '-biphenyl ] -4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (3.35g, 82%).
1H-NMR(400MHz，DMSO)：2.6-2.7(m，1H)，2.9-3.1(m，1H)，3.6-3.75(m，3H)，4.0-4.2(m，1H)，4.2-4.4(m，1H)，4.6(m，0.5H)，5.1(m，0.5H)，5.5(m，2H)，7.4-7.8(m，9H)，9.2-9.4(m，1H)。
Intermediate 9: (2S, 4EZ) -2- (hydrazinecarbonyl) -4- (methoxyimino) -1-pyrrolidinecarboxylic acid tert-butyl ester (scheme 10, Compound XVII)
A solution comprising, for example, (4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2, 17.81mmol, 4.6g) in a 1: 1 mixture of methanol/toluene (250mL) was prepared. Trimethylsilyldiazomethane (32.5mL of a 2M hexane solution, 59mmol) was added dropwise to the solution under nitrogen and with stirring at room temperature. When the nitrogen evolution had ceased, the resulting yellow solution was evaporated in vacuo and the residue was redissolved in DCM and taken up with NH4Saturated solution of Cl, and 10% NaHCO3And saline wash, Na2SO4Drying and subsequent vacuum distillation gave the title compound, (2S, 4EZ) -4- (methoxyimino) -1, 2-pyrrolidinedicarboxylic acid 1-tert-butyl-2-methyl ester (4.0g, 83%) as a yellow oil.
(2S, 4EZ) -4- (methoxyimino) -1, 2-pyrrolidinedicarboxylic acid 1-tert-butyl-2-methyl ester (1.95 mmol; 530mg) was dissolved in 4mL MeOH, and 4mL MeOH and 1.5mL (d ═ 1.03; 30.86mmol) of 80% hydrazine hydrate solution (final concentration (NH.: 1.03; 30.86mmol) were added2NH2) 13%). The reaction mixture was stirred for 2 days. The solvent was evaporated in vacuo and the residue redissolved in MeOH and evaporated (3 ×). The title compound was isolated as a yellow oil, (2S, 4EZ) -2- (hydrazinecarbonyl) -4- (methoxyimino) -1-pyrrolidinecarboxylic acid tert-butyl ester, (500 mg; 94%).
1H-NMR(CDCl3)：1.47(s，9H，CH3)，2.8-3.2(m，2H，CH2)，3.87(s，3H，CH3-O)，3.95-4.3(m，2H，CH2)，4.52(m，1H，CH-N)。MS(APCI+)：273.0，545.4(2M+1)。
Intermediate 10: 2 '-methyl [1, 1' -biphenyl ] -4-carboxylic acid
To a mixture of 4-bromobenzoic acid (30g, 0.15mol), 2-methylbenzeneboronic acid (24g, 0.15mol), sodium carbonate (250g), toluene (500ml) and water (500ml) was added tetrakis-triphenylphosphine palladium (0) (9g, 0.0074mol) under a nitrogen atmosphere. The reaction mixture was refluxed for 10 hours. 100ml of 10% NaOH was then added to the reaction mixture, the aqueous layer was separated and then washed with toluene (2X200mL), the aqueous layer was acidified with 3N HCl solution to give a solid product, filtered, washed with water and dried. The crude product was then recrystallized from toluene to give 2 '-methyl [1, 1' -biphenyl ] -4-carboxylic acid (20g, 62.5%).
Conversely, the product can also be obtained using similar conditions with 1-bromo-2-methylbenzene and 4-carboxyphenylboronic acid.
1H NMR(300MHz，DMSO)：2.2(s，3H)，7.2-7.4(m，4H)，7.43(d，J＝9Hz，2H)，7.99(d，J＝9Hz，2H)，13(b，1H)。
Similarly, using the appropriate commercially available boronic acid and aryl bromide, the following related intermediate 1, 1' -biphenyl derivative (12) was obtained: 4 '-methyl [1, 1' -biphenyl ] -4-carboxylic acid; 2 ', 3-dimethyl [1, 1' -biphenyl ] -4-carboxylic acid; 2 ', 6 ' -dimethyl [1, 1 ' -biphenyl ] -4-carboxylic acid; 2-methyl [1, 1' -biphenyl ] -4-carboxylic acid; 3-methyl [1, 1' -biphenyl ] -4-carboxylic acid; 2, 2 '-dimethyl [1, 1' -biphenyl ] -4-carboxylic acid; 2 '-methoxy [1, 1' -biphenyl ] -4-carboxylic acid; 3 '-methoxy [1, 1' -biphenyl ] -4-carboxylic acid; 4 '-methoxy [1, 1' -biphenyl ] -4-carboxylic acid; 2 '-chloro [1, 1' -biphenyl ] -4-carboxylic acid; 3 '-chloro [1, 1' -biphenyl ] -4-carboxylic acid; 4 '-chloro [1, 1' -biphenyl ] -4-carboxylic acid; 3 ', 4 ' -dichloro [1, 1 ' -biphenyl ] -4-carboxylic acid; 2 '- (trifluoromethyl) [1, 1' -biphenyl ] -4-carboxylic acid; 3 '- (trifluoromethyl) [1, 1' -biphenyl ] -4-carboxylic acid; 2 '-cyano [1, 1' -biphenyl ] -4-carboxylic acid; 2 ', 4 ' -difluoro [1, 1 ' -biphenyl ] -4-carboxylic acid; 4- (2-pyridyl) benzoic acid; 4- (3-pyridyl) benzoic acid; 4- (4-pyridyl) benzoic acid; 4- (5-pyrimidinyl) benzoic acid, and the like.
Intermediate 11: 4- (3-methyl-2-pyridyl) benzoic acid
To 2-bromo-3-methylpyridine (22.5g, 0.1312mol), 4- (hydroxymethyl) phenylboronic acid (25g, 0.164mol), Pd (PPh) under a nitrogen atmosphere3)4(9.5g, 0.0082mol) and sodium carbonate (200g, in 500ml of water) Was refluxed for 15 h. The toluene layer was separated and distilled under reduced pressure to give a residue. The residue was then purified by column chromatography to give [4- (3-methyl-2-pyridyl) phenyl group]Methanol (12g, 47%).
To a solution of [4- (3-methyl-2-pyridyl) phenyl ] -methanol (12g, 0.06mol) in anhydrous DMF (150mL) was added pyridinium dichromate (91g, 0.24moT) and stirred at room temperature for 3 days. The reaction mixture was poured into water and extracted with ethyl acetate (250 mL). The organic layer was washed with water, brine, dried and concentrated. Purification by silica gel column chromatography gave 4- (3-methyl-2-pyridyl) benzoic acid as a white solid (3g, 25%).
1H NMR(300MHz，DMSO)；2.3(s，3H)，7.33(dd，J＝7.5HZ，5Hz，1H)，7.67(d，J＝8Hz，2H)，7.75(d，J＝7.5Hz，1H)，8.01(d，J＝8Hz，2H)，8.50(d，J＝5Hz，1H)，13(b，1H)。
Intermediate 12: 4- (1-oxy-3-pyridyl) benzoic acid
To 4-tolylboronic acid (38g, 0.28mol), 3-bromopyridine (44g, 0.28mol), Na2CO3(200g) Pd (PPh) was added to a mixture of in toluene (500ml) and water (500ml)3)4(16g, 0.014mol) and refluxed for 16 hours. The reaction mixture was cooled, then the organic layer was separated and washed with water and brine, and dried. Removal of the solvent gave 4- (3-pyridyl) toluene (42g, 90%).
To a mixture of 4- (3-pyridyl) toluene (35g, 0.207mol), pyridine (400ml) and water (400ml) was added KMnO in portions4(163g, 1.03mol) and refluxed for 12 hours. The reaction mixture was filtered through celite and acidified with concentrated HCl, the product was washed with water and dried to give 4- (3-pyridinyl) benzoic acid as a white solid (32g, 76%). To a mixture of 4- (3-pyridyl) benzoic acid (22g, 0.11mol) in THF (2.51) was added mCPBA (152g, 0.44mol, 50%) and stirred at room temperature for 12 h. The solid was filtered and washed with THF to give 4- (1-oxo-3-pyridinyl) benzoic acid (20g, 86%).
1H NMR(300MHz，DMSO)；7.5-7.8(m，SH)，7.9(d，J＝8Hz，2H)，8.33(d，J＝5Hz，2H)。
Similarly, starting with 4-tolylboronic acid (45g, 0.33mol) and 2-bromopyridine (52g, 0.33mol), the relevant intermediate 4- (1-oxo-2-pyridinyl) benzoic acid was obtained.
Example 1: general procedure for the liquid phase synthesis of pyrrolidine oxadiazole derivatives of general formula I, wherein B ═ IIa (scheme 1, 11): (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime; (3E, 5S) -1- [ (2 '-methyl [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidone O-methoxime and (3Z, 5S) -1- [ (2 '-methyl [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3 methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidone O-methoxime.
a) Scheme for formation of oxadiazole ring:
diisopropylcarbodiimide (3.16g, 25.17mmol) was added to a solution of (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2, 6.50g, 25.17mmol) and acetamidooxime (intermediate 7, 1.86g, 25.17mmol) in DCM (55ml) and then at room temperature (the DCM insoluble amidoxime was pre-dissolved in THF before adding DIC solution and a solution of intermediate 2 in DCM). After suction filtration and evaporation in vacuo, the residue was dissolved in pyridine (60ml) and refluxed for 1 hour, then cooled overnight, then evaporated in vacuo. The crude product was then dissolved in DCM (50ml) and then NaHCO3(aq) (2x50ml) and further washed with 1m hcl (aq) (2x50ml), dried over magnesium sulphate and evaporated in vacuo (crude yield 70%). Chromatography on silica gel eluting with 15% ethyl acetate/hexanes afforded the title compound, (2S, 4EZ) -4- (methoxy-imino) -2- (3-methyl-1, 2, 4-oxadiazol-5-yl) -1-pyrrolidinecarboxylic acid tert-butyl ester (4.4g, 60% yield).
1H NMR(360MHz，DMSO)；1.3-1.6(d，9H)，2.4(s，3H)，2.8-3.4(m，2H)，3.9(s，3H)，4.3(s，2H)，5.2-5.4(m，1H)。
b) Scheme for N-deprotection step
A solution of tert-butyl (2S, 4EZ) -4- (methoxyimino) -2- (3-methyl-1, 2, 4-oxadiazol-5-yl) -1-pyrrolidinecarboxylate (1.26g, 4.25mmol) in dry DCM (120ml) was prepared. Firstly, with H2SO4The solvent trap was dried, then HCl gas bubbles were slowly bubbled into the reaction at 0 ℃ and deprotection was monitored by Thin Layer Chromatography (TLC) developed using cyclohexane/ethyl acetate (1/1) and pancaldi solution. After about 45 minutes, Thin Layer Chromatography (TLC) showed no starting material remaining, then DCM was evaporated in vacuo and no heat was applied to avoid decomposition of the pyrrolidine salt. DCM (20ml) was then added and again evaporated in vacuo to remove possible residual HCl (2-3 times). The target product, (3EZ, 5S) -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximino, hydrochloride salt, was isolated as a white solid and used without further purification and characterization.
c) Scheme for N-capping step
The method A comprises the following steps: to a solution of (3EZ, 5S) -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl, hydrochloride (200mg, 0.86mmol) in DCM (5ml) was added [1, 1' -biphenyl]-4-carbonyl chloride (205mg, 0.95mmol), then diisopropylethylamine (314. mu.l, 1.81mmol) was added and stirred at room temperature overnight. Aminomethyl polystyrene resin (250mg) was added to the reaction mixture before suction filtration and stirred for 1 hour. The solution was washed with citric acid (aq) (2 × 5ml) and then MgSO4Dried and evaporated in vacuo. Purifying by silica gel chromatography, eluting with 20% ethyl acetate/hexane to obtain the product (3EZ, B) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl. (60mg, 19% yield)
The method B comprises the following steps: preparation of a compound containing (3EZ, 5S) -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl, hydrochloride, 2'-methyl [1, 1' -biphenyl]-4-carboxylic acid (0.857g, 4.04mmol, 0.95eq) and optionally DMAP (1.03g, 8.50mmol.2.0eq) in dry DCM (120 ml). The reaction was stirred at room temperature for 10 minutes and then cooled to 0 ℃. EDC, HCl (815mg, 4.25mmol) was added slowly in portions over 30 min at 0 ℃. The reaction mixture was stirred for 2 hours and slowly warmed to room temperature overnight. Once the reaction was complete, the organic layer was washed twice with citric acid (10%) and sodium carbonate (10%), dried, and the organic phase was evaporated. The crude product was purified by column chromatography (Biotage System, 40M column, 90g SiO)2Cyclohexane/ethyl acetate (1/1) to give (3E, 5S) -1- [ (2 '-methyl [1, 1' -biphenyl) as a colorless oil]-4-yl) carbonyl]-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (770mg, 34%) with a purity of 97.5% by HPLC and (3Z, 5S) -1- [ (2 '-methyl [1, 1' -biphenyl) as a colorless oil]-4-yl) carbonyl]-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl (740mg, 33%) with a purity of 98.3% by HPLC.
(3E, 5S) -1- [ (2 '-methyl [1, 1' -biphenyl)]-4-yl) carbonyl]-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl: an oil;1H NMR(300MHz，CDCl3)：2.28(s，3H，ArCH3)，2.42(s，3H，CH3)，3.03-3.32(m，2H)，3.88(s，3H，NOCH3) 4.38-4.59(m, 2H), 6.03(m, 1H), 7.22-7.29(m, 5H, aryl hydride), 7.40-7.44(m, 2H, aryl hydride), 7.55(m, 1H); MS (APCI)+)：391.5；MS(APCI-)：389.2.
(3Z, 5S) -1- [ (2 '-methyl [1, 1' -biphenyl)]-4-yl) carbonyl]-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl: white solid, m.p.146 ℃, IR (neat) v 2936, 1645, 1583, 1408, 1323, 1047, 890cm "1;1H NMR(300MHz，CDCl3)：2.28(s，3H，ArCH3)，2.42(s，3H，CH3)，3.03-3.32(m，2H)，3.88(s，3H，NOCH3) 4.38-4.59(m, 2H), 6.03(m, 1H), 7.22-7.29(m, 5H, aryl hydride), 7.40-7.44(m, 2H, aryl hydride), 7.55(m, 1H); MS (APC)+)：391.5；MS(APCI-)：389.2
Example 2: (3EZ, 5S) -1- [ (2 '-chloro [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methoxime
Following the general procedure outlined in example 1 (method B), starting from (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), N ' -hydroxyethylimidoamide (intermediate 7) and 2 ' -chloro [1, 1 ' -biphenyl ] -4-carboxylic acid (intermediate 10), flash chromatography gave the title compound E-/Z-isomer as an oily mixture in 31% yield (98.5% purity by HPLC).
An oil;1H NMR(300MHz，CDCl3)：2.41(s，3H，CH3)，2.96-3.31(m，2H，CH2)，3.87(s，3H，NOCH3)，4.31-4.59(m，2H，CH2) 6.03(m, 1H), 7.30(s, 3H, aryl hydrogen), 7.50-7.64(m, 5H, aryl hydrogen); MS (ESI)+)：411.2；MS(ESI-)：408.9。
Example 3: (3EZ, 5S) -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -1- { [2 '- (trifluoromethyl) [1, 1' -biphenyl ] -4-yl ] -carbonyl-3-pyrrolidinone O-methoxime
Following the general procedure outlined in example 1 (method B), starting from (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), N ' -hydroxyethylimidoamide (intermediate 7) and 2 ' - (trifluoromethyl) [1, 1 ' -biphenyl ] -4-carboxylic acid (intermediate 10), flash chromatography gave the title compound as an E-/Z-isomer oily mixture in 44% yield (88.2% purity by HPLC).
An oil;1H NMR(300MHz，CDCl3)：2.40(s，3H，CH3)，2.88-3.31(m，2H，CH2)，3.87(s，3H，NOCH3) 4.27-4.53(m, 2H, CH2), 6.03(m, 1H), 7.27-7.70(m, 7H, arylhydrogen), 7.77(m, 1H, arylhydrogen); MS (ESI)+)：445.4；MS(ESI-)：443.1.
Example 4: (3E, 5S) -1- [ (2 '-fluoro [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methoxime and (3Z.55) -1- [ (2 '-fluoro-1, 1' -biphenyl) -4-yl ] carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methoxime
Following the general procedure shown in example 1 (method B), starting from (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), N ' -hydroxyethylimidoamide (intermediate 7) and 2 ' -fluoro [1, 1 ' -biphenyl ] -4-carboxylic acid (intermediate 10), the title compound was obtained as an E-/Z-isomer mixture, which was then subjected to flash chromatography to give (3E, 5S) -1- [ (2 ' -fluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidone O-methoxime in 11% yield (95.0% purity by HPLC) and 95.0% yield 11% (3Z, 5S) -1- [ (2 '-fluoro [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (98.2% purity by HPLC).
(3E, 5S) -1- [ (2 '-fluoro [1, 1' -biphenyl)]-4-yl) carbonyl]-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl: an oil;1H NMR(300MHz，CDCl3)：2.42(s，3H，CH3)，3.07-3.25(m，2H，CH2)，3.87(s，3H，NOCH3)，4.42-4.52(m，2H，CH2) 6.04(m, 1H), 7.15-7.29(m, 2H, aryl hydrogen), 7.30-7.44(m, 2H, aryl hydrogen), 7.70(m, 4H); MS (ESI)+)：395.0；MS(ESI-)：393.0.
(3Z, 5S) -1- [ (2 '-fluoro [1, 1' -biphenyl)]-4-yl) carbonyl]-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl: an oil;1H NMR(300MHz，CDCl3)：2.42(s，3H，CH3)，3.02(m，1H，CH)，3.25(m，1H，CH)，3.87(s，3H，NOCH3)，4.34-4.58(m，2H，CH2) 6.04(m, 1H), 7.15-7.29(m, 2H, aryl hydrogen), 7.30-7.44(m, 2H, aryl hydrogen), 7.70(m, 4H); MS (ESI)+)：395.0；MS(ESI-)：393.0.
Example 5: (3EZ, 5S) -1- [ (4-fluoro [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4 oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl
Following the general procedure outlined in example 1 (method B), starting from (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), N ' -hydroxyethylimidoamide (intermediate 7) and 4 ' -fluoro [1, 1 ' -biphenyl ] -4-carboxylic acid (intermediate 10), flash chromatography gave the title compound as an E-/Z-isomer oily mixture in 32% yield (94.1% purity by HPLC).
An oil;1H NMR(300MHz，CDCl3)：2.42(s，3H，CH3)，2.95-3.30(m，2H，CH2)，3.87(s，3H，NOCH3)，4.27-4.55(m，2H，CH2) 6.02(m, 1H), 7.12(m, 2H, aryl hydrogen), 7.27-7.61(m, 6H, aryl hydrogen); MS (ESI)+)：395.5；MS(ESI-)：393.4.
Example 6: (3EZ, 5S) -1- [ (2 ' -chloro-4 ' -fluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl 1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime; (3Z, 5S) -1- [ (2 ' -chloro-4 ' -fluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methoxime
Following the general procedure outlined in example 1 (method B), starting from (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), N '-hydroxyethylimidoamide (intermediate 7) and 2' -chloro-4 '-fluoro [1, 1' -biphenyl ] -4-carboxylic acid (intermediate 10), flash chromatography gave the title compound as an oily mixture of E-/Z-isomers in 60% overall yield (95.20% purity by HPLC). Followed by flash chromatography to give (3Z, 5) -1- [ (2 ' -chloro-4 ' -fluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime in 30% yield (97.5% purity by HPLC).
(3EZ, 55) -1- [ (2 ' -chloro-4 ' -fluoro [1, 1 ' -biphenyl)]-4-yl) carbonyl]-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl: an oil;1H NMR(300MHz，CDCl3)：2.31(s，3H，CH3)，2.78-3.24(m，2H，CH2)，3.77(s，3H，NOCH3)，4.30-4.52(m，2H，CH2) (ii) a 5.93(m, 1H), 6.88-7.60(m, 7H, aryl hydrogen); MS (ESI)+)：429.20.
(3Z, 5S) -1- [ (2 ' -chloro-4 ' -fluoro [1, 1 ' -biphenyl)]-4-yl) carbonyl]-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl: an oil;1H NMR(300MHz，CDCl3)：2.31(s，3H，CH3)，2.78-3.24(m，2H，CH2)，3.77(s，3H，NOCH3)，4.30-4.52(m，2H，CH2) 5.93(m, 1H), 6.887.60(m, 7H, aryl hydrogen); MS (ESI)+)：429.20.
Example 7: (3EZ, 5S) -1- [ (2 ', 4 ' -difluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -6- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime; (3Z, 5S) -1- [ (2 ', 4 ' -difluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime; (3E, 5S)1- [ (2 ', 4 ' -difluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime.
Following the general procedure outlined in example 1 (method B), starting from (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), N '-hydroxyethylimidoamide (intermediate 7) and 2', 4 '-difluoro [1, 1' -biphenyl ] -4-carboxylic acid (intermediate 10), flash chromatography gave the title compound as an E-/Z-isomer oily mixture in 37% overall yield (98.6% purity by HPLC). Subsequent separation of the E-/Z-isomer by flash chromatography gave (3Z, 5S) -1- [ (2 ', 4 ' -difluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime in 15% yield (98.5% purity by HPLC), and (3E, 5S) -1- [ (2 ', 4 ' -difluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime in 13% yield (97.5% purity by HPLC).
(3EZ, 5S) -1- [ (2 ', 4 ' -difluoro [1, 1 ' -biphenyl)]-4-yl) carbonyl]-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl: an oil;1H NMR(300MHz，CDCl3)：2.34(s，3H，CH3)，2.86-3.25(m，2H，CH2)，3.79(s，3H，NOCH3)，4.30-4.52(m，2H，CH2) 5.96(m, 1H), 6.82-7.01(m, 2H, aryl hydrogen), 7.32-7.66(m, 5H, aryl hydrogen); MS (ESI)+)：413.40；MS(ESI-)：411.20.
(3Z, 5S) -1- [ (2 ', 4 ' -difluoro [1, 1 ' -biphenyl)]-4-yl) carbonyl]-5- (3-methyl)1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl: an oil;1H NMR(300MHz，CDCl3)：2.31(s，3H，CH3)，2.78-3.24(m，2H，CH2)，3.77(s，3H，NOCH3)，4.30-4.52(m，2H，CH2) 5.93(m, 1H), 6.88-7.60(m, 7H, aryl hydrogen); MS (ESI)+)：413.40；MS(ESI-)：411.20.
(3E, 5S) -1- [ (2 ', 4 ' -difluoro [1, 1 ' -biphenyl)]-4-yl) carbonyl]-5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl: an oil;1H NMR(300MHz，CDCl3)：2.31(s，3H，CH3)，2.78-3.24(m，2H，CH2)，3.77(s，3H，NOCH3)，4.30-4.52(m，2H，CH2) 5.93(m, 1H), 6.88-7.60(m, 7H, aryl hydrogen); MS (ESI)+)：413.40；MS(ESI-)：411.20.
Example 8: (3EZ, 5S) -1- [ (4 ' -fluoro-2 ' -methyl [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl 1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime.
Following the general procedure outlined in example 1 (method B), starting from (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), N '-hydroxyethylimidoamide (intermediate 7) and 4' -fluoro-2 '-methyl [1, 1' -biphenyl ] -4-carboxylic acid (intermediate 10), flash chromatography gave the title compound as an oily mixture of E-/Z-isomers in 14% overall yield (95.2% purity by HPLC).
An oil;1H NMR(300MHz，CDCl3)：2.17(s，3H，CH3)，2.34(s，3H，CH3)，2.86-3.26(m，2H，CH2)，3.80(s，3H，NOCH3)，4.33-4.45(m，2H，CH2) 5.97(m, 1H), 6.82-6.95(m, 2H, aryl hydrogen), 7.10-7.66(m, 5H, aryl hydrogen); MS (ESI)+)：409.33；MS(ESI-)：407.11.
Example 9: (3E, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-carboxim-E: (3Z, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [ (2-hydroxyethyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-methyloxime
Following the general procedure outlined in example 1 (method B), the reaction product was prepared from (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), N ', 3-dihydroxypropanimidamide (intermediate 7) and [1, 1' -biphenyl]Starting from (E) -4-carboxylic acid (intermediate 10), flash chromatography gave the title compound as an oily mixture of E-/Z-isomers in 64% overall yield (90% purity by HPLC). At this point, purification was refined using dcm (novabiochem) of the poly triamine to remove excess acid by-product that could not be removed by flash chromatography. Finally, flash column chromatography (Biotage System, 40M column, 90g SiO)2cyclohexane/Ethyl acetate (2/8) elution) to give (3E, 5S) -1- ([1, 1' -Biphenyl)]-4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1, 2, 4-oxadiazol-5-yl]-3-pyrrolidone O-carboximidoyl in 25% yield (98.0% purity by HPLC), and (3Z, 5) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1, 2, 4-oxadiazol-5-yl]-3-pyrrolidone O-carboximidoyl in 25% yield (99.5% purity by HPLC).
(3E, 5S) -1- ([1, 1' -Biphenyl)]-4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1, 2, 4-oxadiazol-5-yl]-3-pyrrolidone O-methoxime: white solid, mp.140.5;1H NMR(300MHz，CDCl3)：2.98-3.05(m，3H，CH2)，3.33(m，1H，CH2)，3.86(s，3H，OCH3)，4.35-4.57(m，2H，CH2)，6.04(m，1H，CH)，7.38-7.51(m，3H，H-Ar.)，7.51-7.61(m，6H，H-Ar.)：M+(ESI+)：407.31；M(ESI-)：405.13.
(3Z, 5S) -1- ([1, 1' -Biphenyl)]-4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1, 2, 4-oxadiazol-5-yl]-3-pyrrolidone O-methoxime: white solid, m.p.141;1H NMR(300MHz，CDCl3)：2.98-3.05(m，3H，CH2)，3.33(m，1H，CH2)，3.86(s，3H，OCH3)，4.35-4.57(m，2H，CH2)，6.04(m，1H，CH)，7.38-7.51(m，3H，H-Ar.)，7.51-7.61(m，6H，H-Ar.)；M(ESI+)：407.31；M(ESI-)：405.13.
example 10: 2- {5- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-3-yl } ethyl [ (tert-butoxycarbonyl) amino ] -acetate; 2- {5[ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol 3-yl } ethylamino acetate
To the stirred (3Z, 5S) -1- ([1, 1' -biphenyl) at 0 deg.C]-4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1, 2, 4-oxadiazol-5-yl]-3-pyrrolidone O-carboximidoyl (1.59mmol, example 9), dimethylaminopyridine (185mg, 1.51mmol), and [ (tert-butoxycarbonyl) amino [ ]]To a solution of acetic acid (264mg, 1.51mmol) in DCM (50ml) was added EDC (290mg, 1.51mmol) portionwise (over 15 min). The reaction mixture was warmed to room temperature while stirring at 0 ℃ for 1 hour. The reaction was monitored by Thin Layer Chromatography (TLC) and LC/MS. Stirring at room temperature for another 1h, hydrolyzing the reaction mixture with water, rinsing with citric acid 10% (2X10ml), and then with Na2CO3(aqueous) (2X10ml) rinse, MgSO4Drying and vacuum evaporation gave the crude product. Silica gel chromatography, elution with 40% EtOA/cyclohexane gave the title compound, (2- {5- [ (2S, 4EZ) -1- ([1, l' -biphenyl)]-4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl]-1, 2, 4-oxadiazol-3-yl } ethyl [ (tert-butoxycarbonyl) amino group]Acetate) in 90% yield (93.6% purity by HPLC).
M+(ESI+)：564.61；M(ESI-)：562.60
(2- {5- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-3-yl } ethyl [ (tert-butoxycarbonyl) amino ] -acetate) (100ml, 0.178mmol) was treated with 25% TFA/DCM solution at 0 deg.C for 1 hour, then sodium carbonate solution (10%) was added at 0 deg.C to slowly make the reaction basic and extracted with DCM. The organic phases were combined and dried over magnesium sulfate, and the solvent was then removed to give the title compound, 2- {5- [ (2S, 4E-1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) -pyrrolidinyl ] -1, 2, 4-oxadiazol-3-yl } ethylamino acetate, as an oil in 70% yield (94.6% purity by HPLC).
M+(ESI+)：464.17；M(ESI-)：462.86
Example 11: (3EZ, 5S) -1- [ (2 ' -chloro-4 ' -fluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- [3- (2-hydroxyethyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-methyloxime.
Following the general procedure outlined in example 1 (method B), starting from (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), N ', 3-bishydroxypropanimidamide (intermediate 7) and 2' -chloro-4 '-fluoro [1, 1' -biphenyl ] -4-carboxylic acid (intermediate 10), flash chromatography gave the title compound as an E-/Z-isomer oily mixture in 8% overall yield (78.7% purity by HPLC).
An oil;1H NMR(300MHz，CDCl3)：2.93(m，2H，CH2)，3.10-3.25(m，2H，CH2)，3.80(s，3H，NOCH3)，4.34-4.45(m，2H，CH2) 5.98(m, 1H), 6.90-7.05(m, 2H, aryl hydrogen), 7.20-7.66(m, 5H, aryl hydrogen); MS (ESI)+)：459.12；MS(ESI-)：457.07.
Example 12: 4- {5- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-3-yl } -1-piperidinecarboxylic acid tert-butyl ester; (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4 ylcarbonyl) -5- [3- (4-piperidinyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-carboximidoyl.
Following the general procedure shown in example 1 (method A), starting from (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), tert-butyl 4- [ amino (hydroxyimino) methyl ] -1-piperidinecarboxylate (intermediate 7) and [1, 1 '-biphenyl ] -4-carbonyl chloride, flash chromatography (cyclohexane/ethyl acetate 6/4) isolated to give the title compound, E-/Z-containing 4- {5- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-3-yl } -1-piperidinecarboxylic acid tert-butyl ester The mixture was an isomeric oil, with a total yield of 60% (97.9% purity by HPLC).
An oil;1H NMR(300MHz，CDCl3)：1.47(s，9H，CH3)，1.60-2.10(m，4H，CH2)，2.90-3.02(m，-2H，CH2)，3.30-3.40(m，1H，CH)，3.86(s，3H，NOCH3)，4.01-4.55(m，6H，CH2n), 6.03(m, 1H), 7.48-7.64(m, 9H, aryl hydrogen); MS (ESI)+)：546.4；MS(ESI-)：544.2.
Tert-butyl 4- {5- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-3-yl } -1-piperidinecarboxylate (100mg, 1.80mmol) was treated with 25% TFA/DCM solution for 1 hour at 0 deg.C. Sodium carbonate solution (10%) was added to make the reaction alkaline. And then extracted with DCM. The organic phases were combined and dried over magnesium sulfate, the solvent was removed to give a residue which was then purified by flash chromatography eluting with cyclohexane/ethyl acetate (2/8) to give an E-/Z-isomer mixture of (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (4-piperidinyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidone O-methyloxime in 80% yield (96.1% purity by HPLC).
An oil;1H NMR(300MHz，CDCl3)：1.80-2.20(m，4H，CH2)，2.90-3.50(m，8H，CH2)，3.87(s，3H，NOCH3)，4.30-4.60(m，2H，CH2) 6.04(m, 1H, CH), 7.48-7.64(m, 9H, aryl hydrogen); MS (ESI)+)：446.4.
Example 13: (3EZ, 5S) -5- [3- (1-acetyl-4-piperidinyl) -1, 2, 4-oxadiazol-5-yl ] -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-carboximidoyl.
(3EZ, 5S) -1- ([1, 1' -Biphenyl ] -4-ylcarbonyl) -5- [3- (4-piperidinyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-methoxime (example 12) is dissolved in anhydrous DCM in the presence of 1.5 equivalents of triethylamine at 0 deg.C and then treated with 1 equivalent of acetyl chloride. The reaction mixture was stirred at this temperature for 30 minutes and then hydrolyzed with ice. The reaction was made basic with sodium carbonate solution (10%) and then extracted with DCM and dried over magnesium sulfate. Removal of the solvent gave a residue which was purified by flash chromatography eluting with cyclohexane/ethyl acetate (1/1) to give an E-/Z-isomer mixture of (3EZ, 5S) -5- [3- (1-acetyl-4-piperidinyl) -1, 2, 4-oxadiazol-5-yl ] -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidone O-methyloxime in 95% yield (100% purity by HPLC).
An oil;1H NMR(300MHz，CDCl3)：1.70-2.20(m，8H，CH3CO，CH2)，2.89-3.40(m，6H，CH2)，3.88(s，3H，NOCH3)，4.40-4.60(m，2H，CH2) 6.04(m, 1H, CH), 7.48-7.64(m, 9H, aryl hydrogen); MS (ESI)+)：488.37；MS(ESI-)：486.17.
Example 14: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (1-methyl-4-piperidinyl) 1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-carboximidoyl.
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (4-piperidinyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-methoxime (example 12) is dissolved in anhydrous DCM in the presence of 1.5 equivalents of triethylamine at 0 deg.C and then treated with 1 equivalent of iodomethane. The reaction mixture was stirred at room temperature for 12 hours. The reaction was hydrolyzed and made basic with sodium carbonate solution (10%) and then extracted with DCM and dried over magnesium sulfate. Removal of the solvent gave a residue which was purified by flash chromatography eluting with methylene chloride/methanol (98/2) to give an E-/Z-isomer mixture of (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (1-methyl-4-piperidinyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidone O-methyloxime in 50% yield (96.8% purity by HPLC).
An oil;1H NMR(300MHz，CDCl3)：1.19(m，2H，CH2)，2.14-2.70(m，8H，CH3，CH2)，2.89-3.25(m，4H，CH2)，3.80(s，3H，NOCH3)，4.20-4.55(m，2H，CH2) 5.94(m, 1H, CH), 7.337.58(m, 9H, aryl hydrogen); MS (ESI)+)：460.43；MS(ESI-)：458.24.
Example 15: liquid phase synthesis of pyrrolidine oxadiazole derivatives of formula I, B is a substituent of formula IIb (see scheme 7, 11): general procedure for (3EZ, 5S) -1- ([1, 1' -Biphenyl ] -4-ylcarbonyl) -5- [5- (phenoxymethyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl
To (2S, 4EZ) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidinemethanimidamide (intermediate 8, 100mg, 0.28mmol), DMAP (41mg, 0.34mmol), and phenoxyacetic acid (48mg, 0.31mmol) in DCM&EDC (59mg, 0.31mmol) was added to the DMF (1: 1, 10ml) suspension. After stirring at room temperature overnight, the solvent was evaporated in vacuo and the residue was dissolved in DCM (10ml), washed with citric acid (aq) (2x10ml) and then sodium bicarbonate (aq) (2x10 ml). Evaporation was performed in vacuo, pyridine (15ml) was added and the solution was refluxed overnight. Pyridine was removed in vacuo and the residue was dissolved in DCM (10ml), citric acid (aq) (2 × 10ml), dried over magnesium sulphate and evaporated to give the title compound in 80% purity by HPLC. MS (ESI)+)：m/z＝469.2.
Example 16: {3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl-1, 2, 4-oxadiazol-5-yl } methylformamide
Following the general method outlined in example 15, starting with (2S, 4EZ) -1- ([1, 1 '-biphenyl ] -4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and (carboxamido) acetic acid, the title compound was obtained in 72% purity by HPLC.
1H-NMR(400MHz，CDCl3)：2.9-3.2(m，2H)，3.8(m，3H)，4.2-4.4(m，2H)，4.6(m，2H)，5.9(m，1H)，7.0(m，1H)，7.3-7.7(m，9H)，8.2(s，1H)。MS(ESI+)：m/z＝420.1.
Example 17: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (methoxymethyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl
Following the general method outlined in example 15, starting with (2S, 4EZ) -1- ([1, 1 '-biphenyl ] -4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and methoxyacetic acid, the title compound was obtained in 91% purity by HPLC.
1H-NMR(400MHz，CDCl3)：2.9-3.2(m，2H)，3.4(s，3H)，3.75(m，3H)，4.2-4.5(m，2H)，4.6(s，2H)，6.0(m，1H0，7.4-7.6(m，9H)。MS(ESI+)：m/z＝407.2.
Example 18: (3EZ, 5S) -1- ([1, 1' -Biphenyl ] -4-ylcarbonyl) -5- (5-phenyl-1, 2, 4-oxadiazol-3-yl) -3-pyrrolidinone O-carboximidoyl
Following the general procedure outlined in example 15, the reaction product was prepared from (2S, 4EZ) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and benzoic acid as starting materials gave the title compound in 85% purity by HPLC. MS (ESI)+)：m/z＝439.2.
Example 19: n- ({3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } methyl) acetamide
Following the general procedure outlined in example 15, the reaction product was prepared from (2S, 4EZ) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and (acetylamino) acetic acid as starting materials gave the title compound in 72% purity by HPLC. MS (ESI)+)：m/z＝434.2.
Example 20: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [4- (hydroxymethyl) phenyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methoxime
Following the general procedure outlined in example 15, the reaction product was prepared from (2S, 4EZ) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and 4- (hydroxymethyl) benzoic acid as starting materials gave the title compound in 54% purity by HPLC. MS (ESI)+)：m/z＝469.4.
Example 21: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (2-hydroxyethyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl
Following the general procedure outlined in example 15, the reaction product was prepared from (2S, 4EZ) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and 3-hydroxypropionic acid as starting materials to give the titleThe title compound was 61% pure by HPLC. MS (ESI)+)：m/z＝407.2
Example 22: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- [ (2S) -2-hydroxy-2-phenylethyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methyloxime
Following the general procedure outlined in example 15, the reaction product was prepared from (2S, 4EZ) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and (3S) -3-hydroxy-3-phenylpropionic acid as starting materials gave the title compound in 89% purity by HPLC. MS (ESI)+)：m/z＝483.3
Example 23: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (2-phenoxyethyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl
Following the general procedure outlined in example 15, the reaction product was prepared from (2S, 4EZ) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and 3-phenoxypropionic acid as starting materials gave the title compound in 84% purity by HPLC. MS (ESI)+)：m/z＝483.3
Example 24: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (2-methoxyethyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl
Following the general procedure outlined in example 15, the reaction product was prepared from (2S, 4EZ) -1- ([1, 1' -biphenyl)]Starting from (E) -4-ylcarbonyl) -1 (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and 3-methoxypropionic acid, the title compound was obtained in 80% purity by HPLC. MS (ESI)+)：m/z＝421.1
Example 25: (3EZ, 5S) -5- [5- (1-acetyl-4-piperidinyl) -1, 2, 4-oxadiazol-3-yl ] -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-methoxime
Following the general procedure outlined in example 15, the reaction product was prepared from (2S, 4EZ) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and 1-acetyl-4-piperidinecarboxylic acid as starting materials gave the title compound in 87% purity by HPLC. MS (ESI)+)：m/z＝488.4
Example 26: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (2-pyridyl) -1, 2, 4-oxadiazol 3-yl ] -3-pyrrolidinone O-carboximidoyl
Following the general procedure outlined in example 15, the reaction product was prepared from (2S, 4EZ) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and 2-pyridinecarboxylic acid as starting materials gave the title compound in 82% purity by HPLC. MS (ESI)+)：m/z＝440.2
Example 27: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (3-thienyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl
Following the general procedure outlined in example 15, the reaction product was prepared from (2S, 4EZ) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and 3-thiophenecarboxylic acid as starting materials gave the title compound in 64% purity by HPLC. MS (ESI)+)：m/z＝445.2。
Example 28: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (5-ethyl-1, 2, 4-oxadiazol-3-yl) -3-pyrrolidinone O-methyloxime
Following the general procedure outlined in example 15, the reaction product was prepared from (2S, 4EZ) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and propionic acid as starting materials gave the title compound in 47% purity by HPLC. MS (ESI)+)：m/z＝391.1
Example 29: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (5-cyclopentyl-1, 2, 4-oxadiazol 3-yl) -3-pyrrolidinone O-carboximidoyl
Following the general procedure outlined in example 15, the reaction product was prepared from (2S, 4EZ) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and cyclopentanoic acid as starting materials gave the title compound in 62% purity by HPLC. MS (ESI)+)：m/z＝431.1
Example 30: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (5-methyl-1, 2, 4-oxadiazol-3-yl) -3-pyrrolidinone O-methyloxime
Following the general procedure outlined in example 15, the reaction product was prepared from (2S, 4EZ) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and acetic acid as starting materials gave the title compound in 76% purity by HPLC. MS (ESI)+)：m/z＝377.0
Example 31: (3EZ, 5S) -1- ([1, 1' -Biphenyl ] -4-ylcarbonyl) -5- {5- [ (RS) -hydroxy (phenyl) methyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methoxime
Following the general procedure outlined in example 15, the reaction product was prepared from (2S, 4EZ) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and (2RS) -hydroxy (phenyl) glycolic acid as starting materials gave the title compound in 73% purity by HPLC. MS (ESI)+)：m/z＝469.3
Example 32: (3EZ, 5S) -1- ([1, 1' -biphenyl [ -4-ylcarbonyl) -5- {5- [ (1RS) -1-hydroxy-2-phenylethyl-1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methyloxime
Following the general method shown in example 15, the crude product was prepared as (2S, 4EZ) -1- ([1, 1'-biphenyl]-4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and (2RS) -2-hydroxy-3-phenylpropionic acid as starting materials gave the title compound in 78% purity by HPLC. MS (ESI)+)：m/z＝483.3
Example 33: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (1R) -1- (dimethylamino) -2-phenylethyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methyloxime
Following the general procedure outlined in example 15, the reaction product was prepared from (2S, 4EZ) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and (2R) -2- (dimethylamino) -3-phenylpropionic acid as starting materials gave the title compound in 54% purity by HPLC. MS (ESI)+)：m/z＝510.6
Example 34: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (3-pyridyl) -1, 2, 4-oxadiazol 3-yl ] -3-pyrrolidinone O-carboximidoyl
Following the general procedure outlined in example 15, the reaction product was prepared from (2S, 4EZ) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -1V-hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and 3-pyridinecarboxylic acid as starting materials gave the title compound in 78% purity by HPLC. MS (ESI)+)：m/z＝440.2
Example 35: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (6-hydroxy-3-pyridyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl.
Following the general method outlined in example 15, starting with (2S, 4EZ) -1- ([1, 1 '-biphenyl ] -4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and 6-hydroxynicotinic acid, the title compound was obtained in 50% yield and 90% purity by HPLC.
1H NMR(300MHz，CDCl3)：2.90-3.30(m，2H，CH2)，3.86(s，3H，NOCH3)，4.30-4.60(m，2H，CH2) 6.04(m, 1H, CH), 6.70(d, 1H, aryl hydrogen), 7.40-7.70(m, 9H, aryl hydrogen); 8.10(d, 1H, aryl hydrogen), 8.40(d, 1H, aryl hydrogen); MS (ESI)+)：456.4；MS(ESI-)：454.2.
Example 36: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (dimethylamino) methyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-carboxim-ide; (3Z, 5S) -1- ([1, 1' -biphenyl ] -4 ylcarbonyl) -5- {5- [ (dimethylamino) methyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methyloxime; (3E, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (dimethylamino) methyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-carboximidoyl.
Following the general procedure outlined in example 15, starting from (2S, 4EZ) -1- ([1, 1 '-biphenyl ] -4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and (dimethylamino) acetic acid, a mixture of the title compound E-and Z-isomers was obtained in 50% overall yield (96% purity by HPLC). Flash chromatography gave the pure Z-isomer in 23% yield (98.5% purity by HPLC). Pure E-isomer in 20% yield (98.2% purity by HPLC).
(3EZ, 5) -1- ([1, 1' -Biphenyl)]-4-ylcarbonyl) -5- {5- [ (dimethylamino) methyl]-1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-carboximidoyl:1H NMR(300MHz，CDCl3)：2.42(s，6H，CH3)，2.90-3.30(m，2H，CH2)，3.86(s，3H，NOCH3)，4.30-4.60(m，2H，CH2) 6.01(m, 1H, CH), 7.40-7.70(m, 9H, aryl hydrogen); MS (ESI)+)：420.4.
(3Z, 5S) -1- ([1, 1' -Biphenyl)]-4-ylcarbonyl) -5- {5- [ (dimethylamino) methyl]-1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-carboximidoyl:1H NMR(300MHz，CDCl3)：2.42(s，6H，CH3)，2.903.30(m，2H，CH2)，3.86(s，3H，NOCH3)，4.30-4.60(m，2H，CH2) 6.01(m, 1H, CH), 7.407.70(m, 9H, aryl hydrogen); MS (ESI)+)：420.4.
(3E, 5S) -1- ([1, 1' -Biphenyl)]-4-ylcarbonyl) -5- {5- [ (dimethylamino) methyl]-1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-carboximidoyl:1H NMR(300MHz，CDCl3)：2.42(s，6H，CH3)，2.90-3.30(m，2H，CH2)，3.86(s，3H，NOCH3)，4.30-4.60(m，2H，CH2) 6.01(m, 1H, CH), 7.407.70(m, 9H, aryl hydrogen); MS (ESI)+)：420.4.
Example 37: 4- ({3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } methyl) -2, 6-piperazinedione
Following the general method outlined in example 15, starting from (2S, 4EZ) -1- ([1, 1 '-biphenyl ] -4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and (3, 5-dioxo-1-piperazinyl) acetic acid, the title compound was obtained in 55% yield (99.0% purity by HPLC).
1H NMR(300MHz，CDCl3)：2.80-3.30(m，2H，CH2)，3.61(S，4H，CH2)，3.86(s，3H，NOCH3)，4.09(m，2H，CH2)，4.30-4.60(m，2H，CH2) 6.02(m, 1H, CH), 7.42-7.75(m, 9H, aryl hydrogen), 8.56(m, 1H, NH); MS (ESI)+)：489.20；MS(ESI-)：487.17.
Example 38: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [2- (dimethylamino) ethyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methoxime.
Following the general method outlined in example 15, starting from (2S, 4EZ) -1- ([1, 1 '-biphenyl ] -4-ylcarbonyl) -N' -hydroxy-4- (methoxyamino) -2-pyrrolidineiminamide (intermediate 8) and N, N-dimethyl- β -alanine, the title compound was obtained in 25% yield (91.5% purity by HPLC).
1H NMR(300MHz，CDCl3)：2.31(s，6H，CH3)，2.80-3.40(m，6H，CH2)，3.88(s，3H，NOCH3)，4.30-4.60(m，2H，CH2) 6.03(m, 1H, CH), 7.40-7.63(m, 9H, aryl hydrogen); MS (ESI)+)：434.4.
Example 39: (4S) -4- {3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } -4- [ (tert-butoxycarbonyl) amino ] -butyric acid tert-butyl ester.
Following the general method outlined in example 15, starting from (2S, 4EZ) -1- ([1, 1 '-biphenyl ] -4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidinemethanimidamide (intermediate 8) and (2S) -5-tert-butoxy-2- [ (tert-butoxycarbonyl) amino ] -5-oxopentanoic acid, the title compound was obtained in 75% yield (78.9% purity by HPLC).
1H NMR(300MHz，CDCl3)：1.31(s，18H，CH3)，2.05-2.45(m，4H，CH2)，2.70-2.95(m，2H，CH2)，3.87(s，3H，NOCH3)，4.30-4.55(m，2H，CH2) 5.10(m, 1H, CH), 6.03(m, 1H, CH), 7.40-7.63(m, 9H, aryl hydrogen); MS (ESI)+)：620.3，MS(ESI-)：618.3.
Example 40: (3EZ, 5RS) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (1-methyl-3-piperidinyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl.
Following the general method outlined in example 15, starting from (2S, 4EZ) -1- ([1, 1 '-biphenyl ] -4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and 1-methyl-3-piperidinecarboxylic acid, the title compound was obtained in 72% yield (99.2% purity by HPLC).
1H NMR(300MHz，CDCl3)：1.60-1.80(m，3H，CH，CH2)，2.05-2.15(m.2H，CH2)，2.33(s，3H，CH3)；2.92-3.22(m，6H，CH2)，3.84(s，3H，NOCH3)，4.34-4.50(m，2H，CH2) 6.01(m, 1H, CH), 7.38-7.63(m, 9H, aryl hydrogen); MS (ESI)+)：460.5
Example 41: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (1-methyl-4-piperidinyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl.
Following the general method outlined in example 15, starting from (2S, 4EZ) -1- ([1, 1 '-biphenyl ] -4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and 1-methyl-4-piperidinecarboxylic acid, the title compound was obtained in 85% yield (96.9% purity by HPLC).
1H NMR(300MHz，CDCl3)：1.98-2.14(m，5H，CH，CH2)，2.32(s，3H，CH3)，2.89-3.20(m，6H，CH2)，3.86(s，3H，NOCH3)，4.34-4.50(m，2H，CH2) 6.02(m, 1H, CH), 7.38-7.63(m, 9H, aryl hydrogen); MS (ESI)+)：460.4
Example 42: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (5-vinyl-1, 2, 4-oxadiazol-3-yl) -3-pyrrolidinone O-methyloxime.
This compound was obtained in 20% yield (89.4% purity by HPLC) according to the general method shown in example 15 starting from (2S, 4EZ) -1- ([1, 1 '-biphenyl ] -4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and acrylic acid.
1H NMR(300MHz，CDCl3)：2.85-3.15(m，2H，CH2)，3.78(s，3H，NOCH3)，4.28-4.44(m，2H，CH2)，5.89(m，2H，CH)，6.45(d，1H，CH)，6.53(d, IH, CH), 7.30-7.56(m, 9H, aryl hydrogen); MS (ESI)+)：389.2.
Example 43: (3R) -1- {3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } -1-piperidinecarboxylic acid tert-butyl ester; (3EZ, 5S) -1([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (3R) -piperidinyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-carboximidoyl.
This compound, (3R) -3- {3- [ (2S, 4EZ) -1- ([1, 1 '-biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } -1-piperidinecarboxylic acid tert-butyl ester, was obtained in 85% yield (96.5% purity by HPLC) according to the general method as shown in example 15 starting from (2S, 4EZ) -1- ([1, 1I-biphenyl ] -4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and (3R) -1- (tert-butoxycarbonyl) -3-piperidinecarboxylic acid.
MS(ESI+)：546.5.
(3R) -tert-butyl 3- {3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } -1-piperidinecarboxylate (100mg, 1.80mmol) was treated with 25% TFA/DCM solution at 0 deg.C for 1 hour. The reaction was made basic with sodium carbonate solution (10%), extracted with DCM, the organic phases combined, dried over magnesium sulphate and the solvent removed to give a residue which was purified by flash chromatography eluting with dichloromethane/methanol to give the desired product, (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (3R) -piperidinyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methyloxime, mixture of E-/Z-isomers in 80% yield (purity 95.7% by HPLC).
1H NMR(300MHz，CDCl3)：1.62-1.92(m，3H，CH2)，2.20-2.42(m，2H，CH2)，2.75-3.41(m，7H，CH2)，3.86(s，3H，NOCH3)，4.36-4.51(m，2H，CH2) 6.02(m, 1H, CH), 7.40-7.64(m, 9H, aryl hydrogen); MS (ESI)+)：446.2.
Example 44: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (3R) -1-methylpiperidinyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methoxime.
A solution of 1 equivalent of (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (3R) -piperidinyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methoxime (example 43) in anhydrous DCM in the presence of 1.5 equivalents of triethylamine at 0 ℃ is reacted with 1 equivalent of methyl iodide. The reaction mixture was stirred at room temperature for 12 hours, the reaction was hydrolyzed, then sodium carbonate solution (10%) was added to make it basic, and DCM was extracted. The organic layer was then dried over magnesium sulfate and concentrated in vacuo to give a residue which was purified by flash chromatography eluting with methylene chloride/methanol. The desired product was obtained in 45% yield (97.6% purity by HPLC) as a mixture of the E-/Z-isomers of (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- (3R) -1-methylpiperidinyl } -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidone O-methyloxime.
1H NMR(300MHz，CDCl3)：1.61-1.90(m，3H，CH2)，2.01-2.20(m，3H，CH2)，2.23(m，3H，CH3)，2.70-3.30(m.5H，CH2)，3.77(s，3H，NOCH3)，4.30-4.52(m，2H，CH2) 6.01(m, 1H, CH), 7.38-7.70(m, 9H, aryl hydrogen); MS (ESI)+)：460.2.
Example 45: (3S) -3- {3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl) -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } -1-piperidinecarboxylic acid tert-butyl ester; (3EZ, 5S) -1([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (3S) -piperidinyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-carboximidoyl.
Following the general method outlined in example 15, starting from (2S, 4EZ) -1- ([1, 1 ' -biphenyl ] -4-ylcarbonyl) -N ' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and (3S) -1- (tert-butoxycarbonyl) -3-piperidinecarboxylic acid, the title mixture was obtained, (3S) -3- {3- [ (2S, 4EZ) -1- ([1, 1 ' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } -1-piperidinecarboxylic acid tert-butyl ester in 85% yield (97.20% purity by HPLC).
MS(ESI+)：546.5
(3S) -tert-butyl 3- {3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } -1-piperidinecarboxylate (100mg, 1.80mmol) was treated with 25% TFA/DCM solution at 0 deg.C for 1 hour. Sodium carbonate solution (10%) was added to make the reaction basic and extracted with DCM. The combined organic phases were dried over magnesium sulfate and the solvent was removed to give a residue which was purified by flash chromatography eluting with methylene chloride/methanol to give the desired product, an E-/Z-isomer mixture of (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (3S) -piperidinyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidone O-methoxime in 85% yield (95.1% purity by HPLC).
1H NMR(300MHz，CDCl3)：1.62-1.92(m，3H，CH2)，2.20-2.42(m，2H，CH2)，2.75-3.41(m，7H，CH2)，3.86(s，3H，NOCH3)，4.36-4.51(m，2H，CH2) 6.02(m, 1H, CH), 7.40-7.64(m, 9H, aryl hydrogen); MS (ESI)+)：446.2.
Example 46: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (3S) -1-methylpiperidinyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methoxime.
A solution of 1 equivalent of (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (3S) piperidinyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methoxime (example 45) in anhydrous DCM in the presence of 1.5 equivalents of triethylamine at 0 ℃ is reacted with 1 equivalent of methyl iodide. The reaction mixture was stirred at room temperature for 12 hours, the reaction was hydrolyzed, then sodium carbonate solution (10%) was added to make it basic, and DCM was extracted. The organic layer was then dried over magnesium sulfate and concentrated in vacuo to give a residue which was purified by flash chromatography eluting with methylene chloride/methanol. The desired product was obtained in 55% yield (97.9% purity by HPLC) from a mixture of the E-/Z-isomers of (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (3S) -1-methylpiperidinyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methyloxime.
1H NMR(300MHz，CDCl3)：1.61-1.90(m，3H，CH2)，2.01-2.20(m，3H，CH2)，2.33(m，3H，CH3)，2.70-3.30(m.5H，CHa)，3.84(s，3H，NOCH3)，4.30-4.52(m，2H，CH2) 6.01(m, 1H, CH), 7.38-7.70(m, 9H, aryl hydrogen); MS (ESI)+)：460.2.
Example 47: 4- (2- {3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4 (methoxyimino) pyrrolidinyl-1, 2, 4-oxadiazol-5-1 } ethyl) -1-piperazinecarboxylic acid tert-butyl ester
Following the general method outlined in example 15, starting from (2S, 4EZ) -1- ([1, 1 '-biphenyl ] -4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and 3- [4- (tert-butoxycarbonyl) -1-piperazinyl ] -propionic acid, the title compound was obtained in 70% yield (78% purity by HPLC).
1H NMR(300MHz，CDCl3)：1.38(s，9H，CH3)，2.38(m，4H，CH2)，2.70-2.85(m.6H，CH2)，3.34(m，4H，CH2)，3.84(s，3H，NOCH3)，4.23-4.42(m，2H，CH2) 5.92(m, 1H, CH), 7.19-7.53(m, 9H, aryl hydrogen); MS (ESI)+)：575.5.
Example 48: 4- ({3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol 5-yl } methyl) -1-piperazinecarboxylic acid tert-butyl ester; (3EZ, 5S) -1([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (1-piperazinylmethy l) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-carboximidoyl.
Following the general method outlined in example 15, starting from (2S, 4EZ) -1- ([1, 1 ' -biphenyl ] -4-ylcarbonyl) -N ' -hydroxy-4- (methoxyimino) -2-pyrrolidineiminamide (intermediate 8) and [4- (tert-butoxycarbonyl) -1-piperazinyl ] -acetic acid, the title compound, tert-butyl 4- ({3- [ (2S, 4EZ) -1- ([1, 1 ' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } methyl) -1-piperazinecarboxylate, was obtained in 75% yield (88% purity by HPLC).
1H NMR(300MHz，CDCl3)：1.38(s，9H，CH3)，2.38(m，4H，CH2)，2.70-2.85(m.4H，CH2)，3.34(m，4H，CH2)，3.84(s，3H，NOCH3)，4.23-4.42(m，2H，CH2) 5.92(m, 1H, CH), 7.19-7.53(m, 9H, aryl hydrogen); MS (ESI)+)：561.5.
Tert-butyl 4- ({3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } methyl) -1-piperazinecarboxylate (100mg, 1.80mmol) was treated with 25% TFA/DCM solution at 0 deg.C for 1 hour. Sodium carbonate solution (10%) was added to make the reaction basic and extracted with DCM. The organic phases were combined, dried over magnesium sulfate and the solvent was removed to give a residue which was purified by flash chromatography eluting with methylene chloride/methanol to give a mixture of the desired (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (1-piperazinylmethyl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidone O-methyloxime E-/Z-isomers in 85% yield (94.3% purity by HPLC).
1H NMR(300MHz，CDCl3)：2.50(m，4H，CH2)，2.85-2.87(m.4H，CH2)，3.04-3.19(m，2H，CH2)，3.76(s，5H，CH2，NOCH3)，4.27-4.42(m，2H，CH2) 5.94(m, 1H, CH), 7.20-7.54(m, 9H, aryl hydrogen); MS (ESI)+)：461.2.
Example 49: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (4-methyl-1-piperazinyl) methyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methyloxime; (3Z, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (4-methyl-1-piperazinyl) methyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methoxime.
A solution of 1 equivalent of (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (I-piperazinylmeth-yl) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-methoxime (example 48) in anhydrous DCM in the presence of 1.5 equivalents of triethylamine at 0 ℃ is reacted with 1 equivalent of methyl iodide. The reaction mixture was stirred at room temperature for 12 hours, the reaction was hydrolyzed, then sodium carbonate solution (10%) was added to make it basic, and DCM was extracted. The organic layer was then dried over magnesium sulfate and concentrated in vacuo to give a residue which was purified by flash chromatography eluting with methylene chloride/methanol. The desired product was obtained as a mixture of the E-/Z-isomers of (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {5- [ (4-methyl-1-piperazinyl) methyl ] -1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-methyloxime in 50% yield (99.9% purity by HPLC). Flash chromatography gave the pure Z-isomer in 31% yield (98.9% purity by HPLC).
(3EZ, 5S) -1- ([1, 1' -Biphenyl)]-4-ylcarbonyl) -5- {5- [ (4-methyl-1-piperazinyl) methyl]-1, 2, 4 oxadiazol-3-yl } -3-pyrrolidinone O-carboximidoyl:1H NMR(300MHz，CDCl3)：2.32(s，3H，CH3)，2.50-3.20(m，10H，CH2)，3.78-3.92(m，5H，CH2；NOCH3)，4.27-4.45(m，2H，CH2) (ii) a 5.95(m, 1H, CH), 7.32-7.57(m, 9H, aryl hydrogen); MS (ESI)+)：475.2.
(3Z, 5S) -1- ([1, 1' -Biphenyl)]-4-ylcarbonyl) -5- {5- [ (4-methyl-1-piperazinyl) methyl]-1, 2, 4-oxadiazol-3-yl } -3-pyrrolidinone O-carboximidoyl:1H NMR(300MHz，CDCl3)：2.32(s，3H，CH3)，2.50-3.20(m，10H，CH2)，3.78-3.92(m，5H，CH2；NOCH3)，4.27-4.45(m，2H，CH2) 5.95(m, 1H, CH), 7.32-7.57(m, 9H, aryl hydrogen); MS (ESI)+)：475.2.
Example 50: (3EZ, 5S) -5- {5- [ (4-acetyl-1-piperazinyl) methyl ] -1, 2, 4-oxadiazol-3-yl } -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidine O-methyloxime; (3Z, 5S) -5- {5- [ 4-acetyl-1-piperazinyl) methyl ] -1, 2, 4-oxadiazol-3-yl } -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime.
To a solution of 1 equivalent of (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [5- (1-piperazinylmethy-l) -1, 2, 4-oxadiazol-3-yl ] -3-pyrrolidinone O-methoxime (example 48) in anhydrous DCM at 0 deg.C was added 1.5 equivalents of triethylamine and 1 equivalent of acetyl chloride. The reaction mixture was stirred at this temperature for 30 minutes, the reaction was hydrolyzed by the addition of ice, then made basic by the addition of sodium carbonate solution (10%) and extracted with DCM. The organic layer was then dried over magnesium sulfate and the solvent removed to give a residue which was purified by flash chromatography eluting with methylene chloride/methanol. The desired product was obtained as a mixture of the E-/Z-isomers of (3EZ, 5S) -5- {5- [ (4-acetyl-1-piperazinyl) methyl ] -1, 2, 4-oxadiazol-3-yl } -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidone O-methyloxime in 70% yield (94.4% purity by HPLC). Flash chromatography, elution with cyclohexane/ethyl acetate (1: 1) gave the pure Z-isomer in 40% yield (98.0% purity by HPLC).
(3EZ, 5S) -5- {5- [ (4-acetyl-1-piperazinyl) methyl]-1, 2, 4-oxadiazol-3-yl }1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -3-pyrrolidone O-carboximidoyl:1H NMR(300MHz，CDCl3)：2.09(m，3H，CH3)，2.65(S，4H，CH2)，2.90-3.20(m，2H，CH2)，3.54(m，2H，CH2)，3.71(m，2H，CH2)，3.85-3.92(m，5H，CH2；NOCH3)，4.36-4.50(m，2H，CH2) 6.02(m, 1H, CH), 7.40-7.75(m, 9H, aryl hydrogen); MS (ESI)+)：503.2.
(3Z, 5S) -5- {5- [ (4-acetyl-1-piperazinyl) methyl]-1, 2, 4-oxadiazol-3-yl } -1- ([1, 1' -biphenyl)]-4-ylcarbonyl-3-pyrrolidinone O-carboximino:1H NMR(300MHz，CDCl3)：2.09(m，3H，CH3)，2.65(S，4H，CH2)，2.90-3.20(m，2H，CH2)，3.54(m，2H，CH2)，3.71(m，2H，CH2)，3.85-3.92(m，5H，CH2；NOCH3)，4.36-4.50(m，2H，CH2) 6.02(m, 1H, CH), 7.40-7.75(m, 9H, aryl hydrogen); MS (ESI)+)：503.2.
Example 50: 4- { [ (2S, 4EZ) -2- (5- { [ (tert-butoxycarbonyl) amino ] -methyl } -1, 2, 4-oxadiazol-3-yl) -4- (methoxyimino) pyrrolidinyl ] -carbonyl) } -1, 1' -biphenyl
Following the general method outlined in example 15, starting from (2S, 4EZ) -1- ([1, 1 '-biphenyl ] -4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidinemethanimidamide (intermediate 8) and [ (tert-butoxycarbonyl) amino ] -acetic acid, the title compound was obtained in 80% yield (78.2% purity by HPLC).
1H NMR(300MHz，CDCl3)：1.48(s，9H，CH3)，1.58(s，2H，CH2)，2.90-3.43(m，2H，CH2)，3.85(s，3H，NOCH3)，4.20-4.60(m，2H，CH2) 6.03(m, 1H, CH), 7.37-7.63(m, 9H, aryl hydrogen); MS (ESI)+)：492.20，MS(ESI-)：490.2.
Example 51: n- ({3- (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } methyl) -3- (1-piperidinyl) propanamide.
Treatment of 4- { [ (2S, 4EZ) -2- (5- { [ (tert-butoxycarbonyl) amino ] with 25% TFA/DCM solution at 0 deg.C]-methyl } -1, 2, 4-oxadiazol-3-yl) -4 (methoxyimino) pyrrolidinyl]Carbonyl } -1, 1' -biphenyl (example 50), the reaction was followed by LC/MS and stopped after completion. Sodium carbonate solution (10%) was added to make the reaction basic, DCM was extracted, the organic layers were combined, dried over magnesium sulfate and the solvent was removed to give the crude product which was used in the next step without purification. The residue was dissolved in DCM at room temperature, DMAP (1.1 eq) and 3- (1-piperidine) were addedYl) propionic acid (1 equivalent). The reaction mixture was then cooled to 0 ℃ and EDC (1.1 eq) was added dropwise. After stirring at 0 ℃ for 1 hour, the reaction mixture was warmed to room temperature. The reaction was followed by Thin Layer Chromatography (TLC) and LC/MS. Typically, after stirring at room temperature for 12 hours, the reaction mixture is hydrolyzed, washed with sodium carbonate solution (10%), MgSO 24Drying and evaporation in vacuo afforded the crude product which was chromatographed on flash silica, eluting with 60% EtOAc in hexane, to afford a mixture of E-and Z-isomers of the title compound in 50% yield (87.4% purity by HPLC).
MS(ESI+)：531.5；MS(ESI-)：529.2.
Example 52: n- ({3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } methyl) -3- (dimethylamino) propanamide.
Treatment of 4- { [ (2S, 4EZ) -2- (5- ([ (tert-butoxycarbonyl) amino) with 25% TFA/DCM solution at 0 deg.C]-methyl } -1, 2, 4-oxadiazol-3-yl) -4 (methoxyimino) pyrrolidinyl]Carbonyl } -1, 1' -biphenyl (example 50), the reaction was followed by LC/MS and stopped after completion. Sodium carbonate solution (10%) was added to make the reaction basic, DCM was extracted, the organic layers were combined, dried over magnesium sulfate and the solvent was removed to give the crude product which was used in the next step without purification. The residue was dissolved in DCM at room temperature and DMAP (1.1 eq) and N, N-dimethyl- β -alanine (1 eq) were added. The reaction mixture was then cooled to 0 ℃ and EDC (1.1 eq) was added dropwise. After stirring at 0 ℃ for 1 hour, the reaction mixture was warmed to room temperature. The reaction was followed by Thin Layer Chromatography (TLC) and LC/MS. Typically, after stirring at room temperature for 12 hours, the reaction mixture is hydrolyzed, washed with sodium carbonate solution (10%), MgSO 24Drying and evaporation in vacuo afforded the crude product, which was chromatographed on flash silica, eluting with 60% EtOAc in hexanes, to afford the title compoundA mixture of the E-and Z-isomers of (a) in 52% yield (82% purity by HPLC).
MS(ESI+)：491.2.
Example 53: n- ({3- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-5-yl } methyl) -2- (dimethylamino) acetamide.
Treatment of 4- { [ (2S, 4EZ) -2- (5- { [ (tert-butoxycarbonyl) amino ] with 25% TFA/DCM solution at 0 deg.C]-methyl } -1, 2, 4-oxadiazol-3-yl) -4- (methoxyimino) pyrrolidinyl]Carbonyl } -1, 1' -biphenyl (example 50), the reaction was followed by LC/MS and stopped after completion. Sodium carbonate solution (10%) was added to make the reaction basic, DCM was extracted, the organic layers were combined, dried over magnesium sulfate and the solvent was removed to give the crude product which was used in the next step without purification. The residue was dissolved in DCM at room temperature and DMAP (1.1 eq) and (dimethylamino) acetic acid (1 eq) were added. The reaction mixture was then cooled to 0 ℃ and EDC (1.1 eq) was added dropwise. After stirring at 0 ℃ for 1 hour, the reaction mixture was warmed to room temperature. The reaction was followed by Thin Layer Chromatography (TLC) and LC/MS. Typically, after stirring at room temperature for 12 hours, the reaction mixture is hydrolyzed, washed with sodium carbonate solution (10%), MgSO 24Drying and evaporation in vacuo afforded the crude product, which was chromatographed on flash silica, eluting with 60% EtOAc in hexanes, to afford a mixture of E-and Z-isomers of the title compound in 45% yield (88.1% purity by HPLC).
MS(ESI+)：477.25：MS(ESI-)：475.15.
Example 54: 4- { [ (2S, 4EZ) -2- (5- {2- [ (tert-butoxycarbonyl) amino ] -ethyl } -1, 2, 4-oxadiazol-3-yl) -4- (methoxyimino) pyrrolidinyl ] -carbonyl } -1, 1' -biphenyl
This compound was obtained in 75% yield (91.9% purity by HPLC) according to the general method shown in example 15 starting from (2S, 4EZ) -1- ([1, 1 '-biphenyl ] -4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidinemethanimidamide (intermediate 8) and N- (tert-butoxycarbonyl) - β -alanine.
1H NMR(300MHz，CDCl3)：1.36(s，9H，CH3)，2.80-3.15(m，4H，CH2)，3.51(m，2H，CH2)，3.78(s，3H，NOCH3)，4.27-4.42(m，2H，CH2) 5.93(m, 1H, CH), 7.39-7.56(m, 9H, aryl hydrogen); MS (ESI)+)：506.20，MS(ESI-)：504.2.
Example 55: 4- { [ (2S, 4EZ) -2- (5- { (1S) -2-tert-butoxy-1- [ (tert-butoxycarbonyl) amino ] -ethyl } -1, 2, 4-oxadiazol-3-yl) -4- (methoxyimino) pyrrolidinyl ] -carbonyl } -1, 1' -biphenyl; (3EZ, 5S) -5{5- [ (1S) -1-amino-2-tert-butoxyethyl ] -1, 2, 4-oxadiazol-3-yl } -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidone O-methyloxime; (3EZ, 5S) -5- {5- [ (1S) -1-amino-2-hydroxyethyl ] -1, 2, 4-oxadiazol-3-yl } -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime.
Following the general method outlined in example 15, starting from (2S, 4EZ) -1- ([1, 1 '-biphenyl ] -4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidinemethanimidamide (intermediate 8) and (2S) -3-tert-butoxy-2- [ (tert-butoxycarbonyl) amino ] -propanoic acid, the title compound, 4- { [ (2S, 4EZ) -2- (5- { (1S) -2-tert-butoxy-1- [ (tert-butoxycarbonyl) amino ] -ethyl } -1, 2, 4-oxadiazol-3-yl) -4- (methoxyimino) pyrrolidinyl ] -carbonyl } -1, 1' -biphenyl, yield 44% (89.4% purity by HPLC).
MS(ESI+)：578.5.
The reaction was followed by LC/MS for 1 hour at 0 deg.C by treatment of 4- { [ (2S, 4EZ) -2- (5- { (1S) -2-tert-butoxy-1- [ (tert-butoxycarbonyl) amino ] -ethyl } -1, 2, 4-oxadiazol-3-yl) -4- (methoxyimino) pyrrolidinyl ] -carbonyl } -1, 1' -biphenyl (100mg, 1.80mmol) with 25% TFA/DCM solution and stopped after completion. The reaction was made basic by the addition of sodium carbonate solution (10%), extracted with DCM, the organic layers were combined, dried over magnesium sulfate and the solvent was removed to give two products which were purified by flash chromatography on silica gel to give a mixture of the E-and Z-isomers of the title compound: (3EZ, 5S) -5- {5- [ (1S) -1-amino-2-tert-butoxyethyl ] -1, 2, 4-oxadiazol-3-yl } -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-methoxime in 20% yield (80.8% purity by HPLC), and (3EZ, 5S) -5- {5- [ (1S) -1-amino-2-hydroxyethyl ] -1, 2, 4-oxadiazol-3-yl } -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidone O-methoxime in 30% yield (98.1% purity by HPLC).
(3EZ, 5S) -5- {5- [ (1) -1-amino-2-tert-butoxyethyl]-1, 2, 4-oxadiazol-3-yl } -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -3-pyrrolidone O-methoxime:1H NMR(300MHz，CDCl3)：1.07(s，9H，CH3)，1.96(m，2H，NH2)，2.83-3.18(m，2H，CH2)，3.64-3.78(m，5H，CH2，NOCH3)，4.234.43(m，2H，CH2) 5.96(m, 1H, CH), 7.30-7.56(m, 9H, aryl hydrogen); MS (ESI)+)：478.0.
(3EZ, 5S) -5- {5- [ (1S) -1-amino-2-hydroxyethyl]-1, 2, 4-oxadiazol-3-yl } -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -3-pyrrolidone O-carboximidoyl:1H NMR(300MHz，CDCl3)：2.90-3.15(m，2H，CH2)，3.86(s，3H，NOCH3)，4.05-4.42(m，4H，CH2)，4.81(m，1H，CH)，5.89(m，1H，CH)，7.36-7.62(m, 9H, aryl hydrogen); MS (ESI)+)：422.20；MS(ESI-)：420.1.
Example 56: 4- { [ (2S, 4EZ) -2- (5- { (1S, 2R) -2-tert-butoxy-1- [ (tert-butoxycarbonyl) amino ] -propyl } -1, 2, 4-oxadiazol-3-yl) -4- (methoxyimino) pyrrolidinyl ] -carbonyl } -1, 1' -biphenyl; (3EZ, 5S) -5- {5- [ (1S, 2R) -1-amino-2-hydroxypropyl ] -1, 2, 4-oxadiazol-3-yl } -1- ([1, 1' -biphenyl 1-4-ylcarbonyl) -3-pyrrolidone O-methyloxime.
Following the general method outlined in example 15, starting from (2S, 4EZ) -1- ([1, 1 '-biphenyl ] -4-ylcarbonyl) -N' -hydroxy-4- (methoxyimino) -2-pyrrolidinemethanimidamide (intermediate 8) and (2S, 3R) -3-tert-butoxy-2- [ (tert-butoxycarbonyl) amino ] -butyric acid, the title compound, 4- { [2S, 4EZ) -2- (5- { (1S, 2R) -2-tert-butoxy-1- [ (tert-butoxycarbonyl) amino ] -propyl } -1, 2, 4-oxadiazol-3-yl) -4- (methoxyimino) pyrrolidinyl ] -carbonyl } -1, 1' -biphenyl, yield 48% (85.9% purity by HPLC).
MS(ESI+)：592.7
4- { [ (2S, 4EZ) -2- (5- { (1S, 2R) -2-tert-butoxy-1- [ (tert-butoxycarbonyl) amino ] -propyl } -1, 2, 4-oxadiazol-3-yl) -4- (methoxyimino) pyrrolidinyl ] -carbonyl } -1, 1' -biphenyl (100mg, 1.80mmol) was treated with 25% TFA/DCM solution at 0 deg.C for 1 hour, and the reaction was made basic by addition of sodium carbonate solution (10%) and extracted with DCM. The combined organic layers were dried over magnesium sulfate and the solvent was removed to give a residue which was purified by flash chromatography on silica gel eluting with methylene chloride/methanol to give a mixture of E-and Z-isomers of the desired product (3EZ, 5S) -5- {5- [ (1S, 2R) -1-amino-2-hydroxypropyl ] -1, 2, 4-oxadiazol-3-yl } -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime in 30% yield (90.3% purity by HPLC).
1H NMR(300MHz，CDCl3)：1.24-1.35(m，4H，CH3，CH)，2.94-3.25(m，2H，CH2)，3.83(s，3H，NOCH3)，4.22-4.50(m，3H，CH，CH2) 6.01(m, 1H, CH), 7.38-7.60(m, 9H, aryl hydrogen); MS (ESI)+)：436.3.
Example 57: 5- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazole-3-carboxylic acid ethyl ester.
Following the general procedure outlined in example 1 (method B), starting from (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), ethyl amino (hydroxyimino) acetate (intermediate 7) and [1, 1' -biphenyl ] -4-carboxylic acid, flash chromatography gave the title compound as an oily mixture of E-/Z-isomers in 35% yield (96.1% purity by HPLC).
1H NMR(300MHz，CDCl3)：1.35(t，3H)，2.9-3.3(m，2H)，3.8(m，3H)，4.2-4.60(m，4H)，6.01(s，1H)，7.25-7.60(m，9H)；MS(ESI+)：435.3.
Example 58: 5- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -N- [3- (dimethylamino) propyl ] -1, 2, 4-oxadiazole-3-carboxamide
Ethyl 5- [ (2S, 4ES) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazole-3-carboxylate (187mg, 0.43mmol, example 57) was dissolved in 3: 1 THF: water (10ml) and stirred, LiOH (20mg, 0.47mmol, 1.1eq) was added and the mixture was stirred at room temperature for 2 hours. THF was removed in vacuo and the residue was diluted with water and the solution was acidified with 6N HCl (2 drops, pH 5). The aqueous phase was extracted with DCM (2 × 10ml), the organic phase was dried over magnesium sulphate and the solvent was removed in vacuo to give the acid derivative as a yellow oil (165mg, 94%). The crude intermediate (102mg, 0.25mmol) was dissolved in DCM (5mL) and cooled to 0 ℃, EDC · HCl (53mg, 0.28mmol, 1.1eq) was added to the mixture in one portion and the mixture was stirred for 10 min, N', N-dimethyl-1, 3-propanediamine (35mg, 0.28mmol, 1.1eq) was added and the solution was stirred at room temperature overnight. The mixture was washed with 10% aqueous citric acid (2 × 5 mL). The separation effect is poor because the compound is partially soluble in water. The organic solvent was removed in vacuo and the residue was purified by semi-preparative liquid chromatography to give the title compound in 56% yield (93% purity by HPLC).
1H NMR(300MHz，CDCl3)：2.0-2.1(m，2H)，2.8(s，6H)，2.9-3.3(m，4H)，3.5(m，2H)，3.8(m，3H)，4.2-4.60(m，4H)，5.9(s，1H)，7.25-7.65(m，9H)，7.8(m，1H)；MS(ESI+)：491.4.
Example 59: general procedure for solid phase synthesis of pyrrolidine oxadiazole derivatives of general formula I, B substituents of formula IIa (see scheme 13)
a) Addition step
A solution of (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2, 26g, 100mmol) in dry DCM (150ml) was added to Kaiser oxime resin (34.97g, 50mmol) suspended in dry DCM (200 ml). Diisopropylcarbodiimide (7.83ml, 50mmol) was then added to the suspension and shaken at room temperature overnight. The resin was filtered off with suction and washed successively with DMF, DCM and diethyl ether, respectively, and then dried in vacuo at 40 ℃.
b) N-deprotection step
The resin from the addition step was shaken in a 20% trifluoroacetic acid/dichloromethane (200ml) solution for 30 min, then filtered with suction, then washed sequentially with equal amounts of DMF, DCM, diethyl ether and then dried under vacuum at room temperature.
c) N-capping step
The resin from the previous step was placed on a 96-well filter plate (approximately 50mg of anhydrous resin per well) and treated with an N-activated derivatizing reagent on each well. For example, any of the following solutions is used:
a) a solution of acid chloride (0.165mmol) and diisopropylethylamine (0.165mmol) in dry dichloromethane (1ml) overnight
b) Solutions of acid (0.165mmol) and DIC (0.165mmol) in dry dichloromethane or NMP (1ml) overnight, based on the solubility of the carboxylic acid
c) Isocyanate (0.165mmol) in dry THF (1ml) overnight
d) Solution of sulfonyl chloride (0.165mmol) and diisopropylethylamine (0.165mmol) in NMP (1ml) overnight
e) A solution of benzyl (alkyl) bromide (0.165mmol) and diisopropylethylamine (0.165mmol) in NMP (1ml) overnight.
The pan was then sealed and shaken overnight at room temperature. The resin was then filtered, washed successively with equal amounts of DMF, DCM and diethyl ether and then dried in vacuo at room temperature.
d) Cracking step
The amidoxime component (e.g., intermediate 7, 0.27mmol) was added to the suspension of the functionalized oxime resin mass (50mg, 0.05mmol) prepared in the previous step in DCM (0.5-1ml), the disc was sealed and shaken over the weekend at room temperature (-66 hours). After filtration the solvent was evaporated in vacuo, pyridine (0.5-1ml) was added to the residue, the solution refluxed overnight, cooled to room temperature and the solution evaporated in vacuo, and the residue was redissolved in DCM (0.5-1 ml). After washing with 2X0.5-1ml 1MHCl (aq), the solution was dried over magnesium sulphate and evaporated in vacuo to give the crude product which was analysed by HPLC and mass spectrometry. When there is an N-Boc-protecting group on the oxadiazole substituent (e.g. examples 40, 46-48), a solution of 25% TFA in DCM (3ml) is added to the crude product (typically 0.15mmol) and stirred at room temperature for 40 min, and the solvent is removed in vacuo to give the N-deprotected product.
Example 60: (3EZ, 5S) -5- (3-benzyl-1, 2, 4-oxadiazol-5-yl) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime
The general procedure as shown in example 59 was followed to synthesize (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), [1, 1' -biphenyl]-4-carbonyl chloride, and N' -hydroxy-2-phenylethaneimide amide as starting materials, gave the title compound in 86% purity by HPLC. MS (ESI)+)：m/z＝453.2.
Example 61: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (3- { [ (2-furylmethyl) sulfanyl ] -methyl } -1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl
The general procedure as shown in example 59 was followed to synthesize (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), [1, 1' -biphenyl]-4-carbonyl chloride, and 2- [ (2-furylmethyl) sulfanyl]-N' -hydroxyethylimidamide as starting material to give the title compound in 53% purity by HPLC MS (ESI)+)：m/z＝489.6.
Example 62: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ 2-oxo-2- (1 pyrrolidinyl) ethyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methyloxime
The general procedure as shown in example 59 was followed to synthesize (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), [1, 1' -biphenyl]-4-carbonyl chloride, and (1Z) -N' -hydroxy-3-oxo-3- (1-pyrrolidinyl) propanimidamide as starting materials to give the title compound in 89% purity by HPLC. MS (ESI)+)：m/z＝474.2.
Example 63: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ (2-pyridylsulfanyl) methyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methoxime
The general procedure as shown in example 59 was followed to synthesize (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), [1, 1' -biphenyl]-4-carbonyl chloride, and N' -hydroxy-2- (2-pyridylsulfanyl) ethylimidone as starting materials to give the title compound in 66% purity by HPLC. MS (ESI)+)：m/z＝486.2.
Example 64: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (4-fluorophenyl) -1, 2, 4 oxadiazol-5-yl ] -3-pyrrolidinone O-carboximidoyl
The general procedure as shown in example 59 was followed to synthesize (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), [1, 1' -biphenyl]-4-carbonyl chloride, and 4-fluoro-N' -hydroxyphenylmethyliminoamide as starting materials to give the titleThe compound was 79% pure by HPLC. MS (ESI)+)：m/z＝457.2.
Example 65: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ (2-thiophenesulfanylmethyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methoxime
The general procedure as shown in example 59 was followed to synthesize (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), [1, 1' -biphenyl]-4-carbonyl chloride, and N' -hydroxy-2- (2-thienylsulfanyl) ethanamide as starting materials to give the title compound in 81% purity by HPLC. MS (ESI)+)：m/z＝491.4.
Example 66: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [2- (3, 5-dimethyl-1H-pyrazol-1-yl) ethyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methyloxime
The general procedure as shown in example 59 was followed to synthesize (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), [1, 1' -biphenyl]-4-carbonyl chloride, and 3- (3, 5-dimethyl-1H-pyrazol-1-yl) -N' -hydroxypropanimidamide as starting materials. The title compound is obtained in 79% purity by HPLC. MS (ESI)+)：mlz＝485.3.
Example 67: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ (methylsulfonyl) methyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methyloxime
The general procedure as shown in example 59 was followed to synthesize (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), [1, 1' -biphenyl]-4-carbonyl chloride, and N' -hydroxy-2- (methylsulfonyl) ethanamide as starting materials gave the title compound in 87% purity by HPLC. MS (ESI)+)：m/z＝455.2.
Example 68: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (5-methyl-3-isoxazolyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-methyloxime
The general procedure as shown in example 59 was followed to synthesize (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), [1, 1' -biphenyl]-4-carbonyl chloride, and N' -hydroxy-5-methyl-3-isoxazole-carboximidamide as starting materials to give the title compound in 78% purity by HPLC. MS (ESI)+)：m/z＝444.2.
Example 69: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (2-thienylmethyl) -1, 2, 4 oxadiazol-5-yl ] -3-pyrrolidinone O-carboximidoyl
The general procedure as shown in example 59 was followed using (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), [1, 1' -biphenyl]-4-carbonyl chloride, and N' -hydroxy-2- (2-thienyl) ethylimido to give the title compound in 85% purity by HPLC. MS (ESI)+)：m/z＝459.2.
Example 70: (3EZ, 5S) -1- ([1, 1' -Biphenyl ] -4-ylcarbonyl) -5- (3-phenyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl
The general procedure as shown in example 59 was followed to synthesize (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), [1, 1' -biphenyl]-4-carbonyl chloride, and N' -hydroxybenzeneimine amide as starting materials to give the title compound in 82% purity by HPLC MS (ESI)+)：m/z＝439.2.
Example 71: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (3- { [ (2-furylmethyl) sulfonyl ] -methyl } -1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl
The general procedure as shown in example 59 was followed to synthesize (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), [1, 1' -biphenyl]-4-carbonyl chloride, and 2- [ (2-furylmethyl) sulfonyl]-N' -hydroxy-ethyleniminamide as starting material gave the title compound in 88% purity by HPLC. MS (ESI)+)：m/z＝521.4.
Example 72: (3EZ, 5S) -5- [3- (aminomethyl) -1, 2, 4-oxadiazol-5-yl ] -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime
As in example 59General procedure shown with (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), [1, 1' -biphenyl]-4-carbonyl chloride, and (2Z) -2-amino-2- (hydroxyimino) ethylcarbamic acid tert-butyl ester (intermediate 7) as starting materials to give the title compound in 85% purity by HPLC (MS (ESI)+)：m/z＝392.0.
Example 73: (3EZ, 5S) -1- ([1, 1' -Biphenyl ] -4-ylcarbonyl) -5- {3- [ (RS) -hydroxy (phenyl) methyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methoxime
The general procedure as shown in example 59 was followed to synthesize (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), [1, 1' -biphenyl]Starting with (2RS) -N', 2-dihydroxy-2-phenylethaneimide (intermediate 7), 4-carbonyl chloride gave the title compound in 75% purity by HPLC. MS (ESI)+)：m/z＝469.3.
Example 74: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ (1RS) -1-hydroxypropyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methoxime
The general procedure as shown in example 59 was followed to synthesize (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), [1, 1' -biphenyl]Starting from (2RS) -N', 2-dihydroxybutylimide amide (intermediate 7), 4-carbonyl chloride gave the title compound in 79% purity by HPLC. MS (ESI)+)：m/z＝421.2.
Example 75: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (hydroxymethyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-methyloxime
The general procedure as shown in example 59 was followed to start from (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), [1, 1' -biphenyl]-4-carbonyl chloride, and N', 2-dihydroxyethyleneimine amide (intermediate 7) to give the title compound in 85% purity by HPLC. MS (ESI)+)：m/z＝393.0.
Example 76: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ (1S, 2R) -2-hydroxycyclohexyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methyloxime
The general procedure as shown in example 59 was followed to synthesize (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), [1, 1' -biphenyl]Starting from (4) -carbonyl chloride and (1S, 2R) -N', 2-dihydroxycyclohexane-carboximidamide (intermediate 7), the title compound was obtained in 85% purity by HPLC. MS (ESI)+)：m/z＝461.2.
Example 77: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ (3RS) -piperidinyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-carboximidoyl
The general procedure as shown in example 59 was followed to synthesize (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methyl) carbonylOxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), [1, 1' -biphenyl]-4-carbonyl chloride, and (3RS) -3- [ amino (hydroxyimino) methyl]Tert-butyl-1-piperidinecarboxylate (intermediate 7) as starting material gave the title compound in 77% purity by HPLC. MS (ESI)+)：m/z＝446.2.
Example 78: (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ (2RS) -piperidinyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-carboximidoyl
The general procedure as shown in example 59 was followed to start from (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidine-carboxylic acid (intermediate 2), [1, 1' -biphenyl]-4-carbonyl chloride, and (2RS) -2- [ amino (hydroxyimino) methyl]-tert-butyl 1-piperidinecarboxylate (intermediate 7) to give the title compound in 78% HPLC purity. MS (ESI)+)：m/z＝446.2.
Example 79: a liquid phase synthesis of pyrrolidine oxadiazole derivatives of formula I (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (5-thio-4, 5-dihydro-1, 3, 4-oxadiazole 2-yl) -3-pyrrolidone O-methyloxime, wherein B is a substituent of formula III and X ═ S (scheme 9, 11)
To a solution of tert-butyl (2S, 4EZ) -2- (hydrazinecarbonyl) -4- (methoxyimino) -1-pyrrolidinecarboxylate (intermediate 9, 2.86 mmol; 780mg) in ethanol (25mL) at 0 deg.C was added carbon disulfide (6.86 mmol; 522mg) and potassium hydroxide (3 mmol; 168 mg). The mixture was refluxed for 7 hours. The solvent was evaporated and the residue was redissolved in EtOAc, then saturated NH4Cl and 10% NaHCO3And washing with saline, Na2SO4The organic layer was dried and evaporated to give the desired N-protected intermediate, (tert-butyl 2S, 4EZ) -4- (methoxyimino) -2- (5-thio-4, 5-dihydro-1, 3, 4-oxadiazol-2-yl) -1-pyrrolidinecarboxylate, as a yellow oil, (200mg, 23%).
1H-NMR(CDCl3)：1.46(m，9H，CH3)，2.7-3.3(m，2H，CH2)，3.88(s，3H，CH3-O)，4.05-4.35(m，2H，CH2)，5.29(m，1H，CH-N)。MS(APCI-)：313.0.
The N-protected intermediate from the previous step, (2S, 4EZ) -4- (methoxy-imine) -2- (5-thio-4, 5-dihydro-1, 3, 4-oxadiazol-2-yl) -1-pyrrolidinecarboxylic acid tert-butyl ester (0.64 mmol; 200mg) was dissolved in anhydrous DCM (25mL) at 0 deg.C and HCl gas was blown into the solution for 20 minutes, the solvent was evaporated and the residue was redissolved in DCM and evaporated. The residue was again dissolved in anhydrous DCM (20mL) and triethylamine (5.12 mmol; 518mg) was added, followed by slow addition of the N-capping reagent, e.g., [1, 1' -biphenyl, pre-dissolved in DCM]4-carbonyl chloride (0.64 mmol; 139 mg). The reaction mixture was stirred at room temperature overnight, then 200mg of a poly-triamine (3.45mmol/g) was added to the mixture to scavenge the acid chloride, the reaction was stirred for an additional 5 hours, then filtered and the filtrate saturated with NH4Cl solution and brine, Na2SO4Drying and evaporating the solvent. The crude product was purified by flash chromatography with a linear gradient of 40: 60 (EtOAc: cyclohexane) to 90: 10 (EtOAc: MeOH) for 37 minutes to give the title compound (3EZ, 5S) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -5- (5-thio-4, 5-dihydro-1, 3, 4-oxadiazol-2-yl) -3-pyrrolidinone O-carboxim-e (40mg, 16%).
1H-NMR(CDCl3)：2.8-3.2(m，2H，CH2)，3.9(s，3H，CH3-O)，4.2-4.5(m，2H，CH2)，5.95(m，1H，CH-N)，7.3-7.7(m，9H，Ar)。MS(APCI+)：395.0；MS(APCI-)：393.0.
Example 80: liquid phase synthesis of pyrrolidine oxadiazole derivatives of general formula I, wherein B ═ III, X ═ O (scheme 9, 11): general procedure for 5- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 3, 4-oxadiazol-2 (3H) -one
To a solution of tert-butyl (2S, 4EZ) -2- (hydrazinecarbonyl) -4- (methoxyimino) -1-pyrrolidinecarboxylate (intermediate 9, 1.84 mmol; 500mg) and triethylamine (2.76 mmol; 279mg) in THF (25mL) at 0 deg.C was added 1, 1' -carbonyldiimidazole (2.76mmol, 448 mg). Stirring was continued for 5 hours, another portion of triethylamine and 1, 1' -carbonyldiimidazole was added and stirring was continued overnight at room temperature. The solvent was evaporated, the residue dissolved in EtOAc and washed with NH4Saturated aqueous solution of Cl, and 10% NaHCO3And a saline flush. The organic layer is coated with Na2SO4Drying and evaporation to dryness gave the desired N-protected intermediate, (tert-butyl 2S, 4E) -4- (methoxyimino) -2- (5-oxo-4, 5-dihydro-1, 3, 4-oxadiazol-2-yl) -1-pyrrolidinecarboxylate, as a white foam (460mg, 84%).
1H-NMR(CDCl3)：1.46(s，9H，CH3)，2.8-3.25(m，2H，CH2)，3.88(s，3H，CH3-O)，4.054.35(m，2H，CH2)，5.06(m，1H，CH-N)。MS(APCI-)：297.0.
The N-protected intermediate obtained in the previous step, tert-butyl (2S, 4) -4- (methoxyimino) -2- (5-oxo-4, 5-dihydro-1, 3, 4-oxadiazol-2-yl) -1-pyrrolidinecarboxylate, was subjected to the same N-deprotection conditions followed by N-acylation to give the title compound (5- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) -pyrrolidinyl ] -1, 3,4 oxadiazol-2 (3H) -one (130mg, 26%) after flash chromatography purification as described in example 49.
1H-NMR(CDCl3)：2.8-3.1(m，2H，CH2)，3.84(s，3H，CH3-O)，4.2-4.5(m，2H，CH2)，5.75(m，1H，CH-N)，7.35-7.7(m，9H，Ar)。MS(APCI+)：379.0；MS(APCI-)：377.0.
Example 81: liquid phase synthesis of formula I wherein B is a substituent of formula IV, X ═ bond, R8Pyrrolidine oxadiazole derivative of ═ H: (3EZ, 5S) -1- ([1, 1' -Biphenyl)]General procedure for (E) -4-ylcarbonyl) -5- (1, 3, 4-oxadiazol-2-yl) -3-pyrrolidinone O-carboximidoyl (schemes 9, 11)
To a solution of (2S, 4EZ) -2- (hydrazinecarbonyl) -4- (methoxyimino) -1-pyrrolidinecarboxylic acid tert-butyl ester (intermediate 9, 2.86 mmol; 780mg) in TMOF (8mL) was added 3 drops of acetic acid and the reaction mixture was heated to 80 ℃ for 4h, then at room temperature overnight, and the anhydrous solvent was evaporated to give a yellow foam (610 mg). The residue is dissolved in toluene and P is added2O5The reaction mixture was heated to reflux for 2.5 hours, after which the solvent was evaporated. Water was added to the residue and the solution was extracted with EtOAc. By NH4The organic layer was washed with saturated aqueous Cl and brine to afford the desired N-protected intermediate, tert-butyl (2S, 4E) -4- (methoxyimino) -2- (1, 3, 4-oxadiazol-2-yl) -1-pyrrolidinecarboxylate, as a yellow oil (330mg, 63%).1H-NMR-analysis showed the product to be > 90% pure. The compound was considered sufficiently pure to be used in subsequent steps without further purification (only 2 spots on thin layer chromatography, Pancaldi color, corresponding to E-and Z-isomers, Rf ═ 0.35 and 0.47, EtOAc: hexane 1: 1 elution).
1H-NMR(CDCl3): 1.46 (broad multimodal, 9H, CH)3)，2.8-3.3(m，2H，CH2)，3.89(s，3H，CH3-O)，4.05-4.3(m，2H，CH2)，5.4(m，1H)，CH-N)。MS(APCI+)：283.0.
The N-protected intermediate obtained in the previous step, tert-butyl (2S, 4E) -4- (methoxyimino) -2- (1, 3, 4-oxadiazol-2-yl) -1-pyrrolidinecarboxylate, was subjected to the same N-deprotection conditions followed by N-acylation to give the title compound (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (1, 3, 4-oxadiazol-2-yl) -3-pyrrolidinone O-methyloxime (80mg, 10%) after flash chromatography as described in example 49.
1H-NMR(CDCl3)：2.8-3.2(m，2H，CH2)，3.65(s，3H，CH3-O)，4.2-4.45(m，2H，CH2) 5.95(m, 1H, CH-N), 7.3-7.6(m, 9H, Ar), 8.2(s, 1H, CH hetero). MS (APCI)+)：363.4.
Example 82: liquid phase synthesis of formula I, wherein B is of formula IIb, R7Pyrrolidine oxadiazole derivative of ═ H: (3EZ, 5S) -1- ([1, 1' -Biphenyl)]General procedure for (E) -4-ylcarbonyl) -5- (1, 2, 4-oxadiazol-3-yl) -3-pyrrolidinone O-carboximidoyl
To (2S, 4EZ) -1- ([1, 1' -biphenyl)]To a suspension of (E) -4-ylcarbonyl) -N' -hydroxy-4- (methoxy-imine) -2-pyrrolidineiminamide (intermediate 8, 170mg, 0.48mmol) in TMOF (20ml) was added a catalytic amount of p-toluene sulfonic acid, the reaction mixture was heated to reflux for 16 h, then TMOF was evaporated in vacuo, the residue was dissolved in DCM (15ml) and purified with NaHCO3(aqueous) (2X 15ml) rinse, MgSO4Drying, vacuum evaporation, silica gel chromatography, elution with 15% EtOAc/hexanes to provide the desired product (3EZ, 5S) -1- ([1, 1' -biphenyl)]-4-ylcarbonyl) -5- (1, 2, 4-oxadiazol-3-yl) -3-pyrrolidinone O-carboximidoyl (59 mg).
1H-NMR(400MHz，CDCl3)：2.9(m，1H)，3.2(m，1H)，3.9(m，3H)，4.3-4.6(m，2H)，6.1(m，1H)，7.3-7.7(m，9H，8.7(s，1H)。MS(API)：363.2.
Example 83: preparation of pharmaceutical formulations
Formulation 1-tablet
The pyrrolidine oxadiazole compound of formula I is mixed with an anhydrous gel binder in a weight ratio of about 1: 2 to form a dry powder. A small amount of magnesium stearate was added as a lubricant. The mixture was made into 240-270mg tablets (each containing 80-90mg of the active pyrrolidine oxadiazole compound) in a tablet press.
Preparation 2-capsule
The pyrrolidine oxadiazole compound of formula I is mixed with a starch diluent in a weight ratio of about 1: 1 to form a dry powder. The mixture was filled into 250mg capsules (each containing 125mg of the active pyrrolidine oxadiazole compound).
Preparation 3-liquid preparation
The pyrrolidine oxadiazole compound of formula I was mixed with sucrose and xanthan gum, passed through a 10 mesh U.S. standard sieve, and then mixed with a previously prepared aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11: 89). Sodium benzoate diluted with water, flavoring and coloring were added and stirred, then enough water was added.
Formulation 4-tablet
The pyrrolidine oxadiazole compound of formula I is mixed with the anhydrous gel binder in a weight ratio of about 1: 2 to form a dry powder. A small amount of magnesium stearate was added as a lubricant. The mixture was prepared into 450-900mg tablets (each containing 150-300mg of the active pyrrolidine oxadiazole compound) in a tablet press.
Preparation 5-injection
Pyrrolidine oxadiazole compounds of general formula I are dissolved in aqueous media in buffered sterile saline injectable to give satisfactory concentrations.
Example 84: biological activity assay
The compounds of the formula I can be tested as follows
a) In vitro competitive binding assays using scintillation proximity assays (Pharmaceutical manufacturing International, 1992, p.49-53, Cook, N.D. et al)
This assay is capable of determining the affinity of the tested compounds for the OT receptor. HEK293EBNA cell membranes expressing the hOT receptor were resuspended in a medium containing 50mM Tris-HCl, pH7.4, 5mM MgCl2And 0.1% BSA (w/v) in buffer. The membrane (2-4 μ g) was mixed with 0.1mg of malt agglutinin (WGA) SPAA bead (type A) and 0.2nM of radioactive label [ alpha ], [125I]OVTA (OVTA is a vasoactive ornithine and is an OT analogue known for competition binding response assays). Nonspecific binding was determined in the presence of 1 μ M oxytocin. The total test volume was 100. mu.l. Incubating the plate at room temperature (NBS plate) for 30 minutes and counted on a Mibro-beta-plate counter. The compounds tested were used at concentrations of 30. mu.M, 10. mu.M, 1. mu.M, 300nM, 100nM, 10nM, 1nM, 100pM, 10 pM. Competition binding data was analyzed using the iterative, nonlinear, curve fitting program "Prism".
The binding affinity of the pyrrolidine derivatives of formula I to the oxytocin receptor was evaluated using the in vitro bioassay described above. Representative values for some of the example compounds are given in table I below. These data refer to the binding affinity (IC) of the compounds of formula I for the oxytocin receptor in the examples50；μM)
Table 1:
according to a preferred embodiment, the compounds exhibit binding affinity (IC)50(μ M)) is less than 0.40 μ M, more preferably less than 0.1 μ M.
b) Functional test No. 1: inhibition of Ca2+Flow through, use FLIPR (fluorescence imaging plate reader)
FLIPR is a device that can rapidly measure large numbers of samples by using a machine that performs fluorescence imaging using a laser capable of illuminating a 96-well plate and reading each well simultaneously
This test was intended to show that OT/OT-R mediated Ca, which is necessary for causing uterine contractions, is mediated by the use of a test compound of the general formula (I)2+Inhibition of circulation.
Preparation of the plate: PLL (poly-L-lysine) 10. mu.g/ml + 0.1% gel was pre-coated on FLIPR plates at 37 ℃ to attach HEK (human embryonic kidney) cells for 30 minutes to 2 days, and the cells were plated onto 96-well plates (60000 cells/well).
Labeling with fluo-4: mu.g of fluo-4 (fluorescent marker) was dissolved in 20. mu.l of Pluronic acid (20% dimethylsulfoxide solution). The solubilized fluo-4 was then removed from the plate with 10. mu.l DMEM (Dubecco's minimal essential medium without FCS-F12 medium), followed by rinsing once with DMEM-F12 medium. At this point, 100ml of DMEM-F12 medium containing fluo-4 was added and the cells were incubated for 1-1.5 hours (CHO-cells), 1.5-2 hours (human embryonic kidney-cells). The cells now contain a fluorescent marker.
Buffer solution: 145mM NaCl, 5mM KCl, 1mM MgCl210mM Hepes, 10mM glucose, EGTA (ethylene-dioxyethylene nitrilo tetraacetic acid), adjusted to pH 7.4.
The implementation of the test: a minimum of 80. mu.l/well of antagonist (5X) of the above buffer solution (1X) was prepared (96-well plate). Antagonists were added to the well plates at different concentrations (30. mu.M, 10. mu.M, 1. mu.M, 300nM, 100nM, 10nM, 1nM, 100pM, 10 pM).
OT was added at a concentration of 40 nM.
Fluorescent marker on intracellular Ca2+The flux is sensitive and can be quantified by the FLIPR device.
The activity of the pyrrolidine derivatives of general formula I was evaluated using the in vitro bioassay described above. Typical values for some of the example compounds are given in table 2 below. These values indicate that the compounds of the example of formula I are effective in antagonizing oxytocin-induced oxytocin receptor-mediated intracellular Ca2+Ability to circulate.
Table 2:
c) functional test No. 2: inhibition of IP3 (inositol triphosphate) synthesis in HEK/EBNA-OTR cells
This test was intended to show the inhibitory effect on the OT/OT-R mediated synthesis of IP3 necessary for uterine contractions by using the test compound of the general formula (I).
Stimulation of cells: HEK/EBNAOTR (murine or human) cells were plated into costar 12-well plates and radiolabeled with 1% FCS (0.5 ml/well) without inositol supplement3H]-inositol equilibration for 15-24 hours. 4uCi/ml was used. The medium containing the marker is then aspirated. DMEM (without FCS, inositol), 20mM Hepes (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid), 1mg/ml BSA with 10M LiCl (fresh) was then added over 10-15 min at 37 deg.C. At the desired time (15-45 min) agonists (e.g. oxytocin at a concentration of 10 nM) and antagonists (test compounds of general formula (I) at a concentration of 10. mu.M, 1. mu.M, 300nM, 100nM, 10nM, 1nM, 100pM, 10pM, 3 pM) were added and the culture aspiratedAnd (5) nutrient base. Radiolabelled inositol is phosphorylated to IP3 due to antagonism of the OT receptor, and radiolabelled IP can be judged by follow-up examination3The amount of (c). The reaction was stopped using 1ml of STOP-solution (i.e., 0.4M perchloric acid) and allowed to stand at room temperature for 5-10 minutes. Then 0.8ml was poured into a solution containing 0.4ml of a neutralizing solution (0.72M, KOH/0.6M KHCO)3) The test tube of (a), a vortex is formed in the test tube and kept cool for at least 2 hours. Isolation of IP's: the samples were placed on a tabletop centrifuge and centrifuged at 3000-. Then 1ml of the supernatant was poured into a container containing 2.5ml of H2In O-fresh tubes, the encapsulated resin (0.8ml) was equilibrated with 20ml of water, and the entire sample was poured into a chromatographic column to separate the mixture. With 10ml of H2O rinse twice to remove free inositol.
Elution of total IP's: elution was carried out using 3ml ammonium formate/0.1M formic acid. The eluent was collected in scintillation counting tubes, followed by the addition of 7ml of scintillation fluid. The amount of IP3 was measured using a scintillation counter.
d) In vivo model for inhibiting uterine contraction
This test seeks to show the physiological activity of the test compounds in models of in vivo abortion and preterm birth.
At 18 and 24 hours prior to the assay, the non-pregnant Charles River CD (SD) BR female (9-10 weeks old, 200-. For the test, animals were anesthetized with carbamate (1.75g/kg, i.p.) and then placed on a thermostated operating table. The organ is isolated and inserted into a suitable Polyethylene (PE) tube. After making a midline incision at the level of the abdomen and exposing a corner of the uterus, and filling the lumen with 0.2ml of sterile saline, a PE240 tube was inserted at the end of the head and connected to a "Gemini" amplification/recording system via a P23 ID GouldStatha pressure transducer. For the i.v route of administration of the compounds, one jugular vein was isolated and a PE60 tube attached to a butterfly needle was inserted for administration using a syringe. For duodenal administration of test compounds, the duodenum is isolated and similarly cut into the wall. The carotid artery was closed and cannulated with PE60 catheter and then connected to a suitable syringe to collect blood samples (see below). After a period of stabilization, the same dose of oxytocin was repeatedly injected every 30 minutes. When comparable contractile responses of the uterus to the selected dose of oxytocin were obtained, the compounds were tested at 0.3; 1; 3; 10mg/kg (5ml/kg infusion; i.v.) and 30mg/kg (7, 5ml/kg infusion; i.v), and 3 and 10mg/kg (5 ml/kg; oral), 30mg/kg (7, 5 ml/kg; oral) and 60mg/kg (10 ml/kg; oral). The same dose of oxytocin was reinjected at the appropriate time after treatment to evaluate the inhibitory effect of the compound in question. The contractile response of oxytocin to the uterus was quantified by measuring intrauterine pressure and number of contractions.
Groups of six animals were treated with the test compounds at the indicated concentrations (see above)
The effect of the test compound was evaluated by comparing the pressure values before and after treatment. In addition, 0.5ml blood samples were taken from the cannulated carotid artery of each test animal 2, 30, 90 and 210 minutes after administration of the test compound. Plasma was obtained by standard laboratory study methods and stored at-20 ℃.
The activity of the pyrrolidine derivatives of general formula I was determined using the in vivo bioassay described above. Representative data for one example compound is given in table 3 below. These data represent the ability of the compounds of formula I of the examples to effectively antagonize oxytocin-induced uterine contractions in mice.
Table 3:

Claims (17)

1. Pyrrolidine oxadiazole derivatives of the general formula I:
and pharmaceutically acceptable salts thereof, wherein:
a is- (C ═ O) -;
b is 1, 2, 4-oxadiazole;
R1is C1-C6-an alkyl group;
R2is aryl, which may be further fused with 1-2 aryl groups;
R3’、R4、R5and R6Independently selected from hydrogen, halogen, C1-C6-alkyl, or C1-C6-alkoxy groups.
2. The pyrrolidine oxadiazole derivative of claim 1, wherein R is1is-CH3。
3. A pyrrolidine oxadiazole derivative according to claim 1, wherein R is2Is phenyl.
4. A pyrrolidine oxadiazole derivative according to claim 3, wherein said phenyl group is substituted with a phenyl group.
5. A pyrrolidine oxadiazole derivative according to claim 1, wherein B is an oxadiazole of formula IIa:
wherein R is7Selected from hydrogen, sulfonyl, amino, C1-C6-alkyl radical, C2-C6-alkenyl, C2-C6-alkynyl, wherein the alkyl, alkenyl, alkynyl chain may be interrupted by heteroatoms selected from N, O or S, aryl, heteroaryl, saturated or unsaturated 3-8-membered cycloalkyl, heterocycloalkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be further fused with 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups, an acyl residue, C1-C6-alkylaryl group, C1-C6Alkyl heteroaryl radical, C1-C6Alkenylaryl radical, C1-C6Alkenyl heteroaryl, C1-C6-an alkynylaryl group,C1-C6-alkynylheteroaryl, C1-C6Alkyl cycloalkyl radical, C1-C6Alkyl heterocycloalkyl radical, C1-C6Alkenylcycloalkyl radical, C1-C6Alkenyl heterocycloalkyl, C1-C6Alkynylcycloalkyl, C1-C6Alkynyl heterocycloalkyl, alkoxycarbonyl, aminocarbonyl, C1-C6-alkylcarboxy radical, C1-C6Alkanoyl, aryloyl, heteroarylacyl, C3-C8(hetero) cycloalkylacyl radical, C1-C6-alkanoyloxy, C1-C6Alkyl alkoxy, C1-C6Alkyl alkoxycarbonyl, C1-C6-alkylaminocarbonyl radical, C1-C6Alkylamido, acylamino, C1-C6-alkylureido, C1-C6Alkyl carbamates, C1-C6-alkylamino radical, C1-C6An alkylammonium group, C1-C6Alkylsulfonyloxy, C1-C6-alkylsulfonyl, C1-C6-alkylsulfinyl radical, C1-C6Alkyl sulfanyl radical, C1-C6-alkylsulfonylamino, C1-C6Alkylaminosulfonyl, hydroxy or halogen.
6. The pyrrolidine oxadiazole derivative of claim 5, wherein R7Selected from sulfonyl or amino residues, or C1-C6-alkyl radical, C2-C6Alkenyl radical, C2-C6-alkynyl, aryl, heteroaryl, 3-8 membered cycloalkyl optionally containing at least one heteroatom selected from N, O, S, C1-C6-alkylaryl group, C1-C6Alkyl heteroaryl radical, C1-C6Alkenylaryl radical, C1-C6Alkenyl heteroaryl, alkoxycarbonyl, carboxylic acid amide, C1-C6-alkylcarbonyl, arylcarbonyl or heteroarylcarbonyl, C4-C8Cycloalkylcarbonyl, said radical being substituted by at least one sulfonyl groupOr an amino residue.
7. A pyrrolidine oxadiazole derivative according to claim 6, wherein R is7Is selected from C1-C6Alkylamino, heterocycloalkyl, C1-C6Alkyl heterocycloalkyl, aminocarbonyl, C1-C6Alkylaminocarbonyl radical, C1-C6Alkyl amido radical, C1-C6Alkylsulfonyl or C1-C6-an alkyl group.
8. A pyrrolidine oxadiazole derivative according to claim 7, wherein R is7Selected from dimethylaminomethyl, 2- (dimethylamino) ethyl, 1-methyl-3-piperidinyl or 4- (acetyl-1-piperazinyl) methyl.
9. A pyrrolidine oxadiazole derivative according to any of the preceding claims, wherein each R3’R4’R5And R6Is H.
10. A pyrrolidine oxadiazole derivative according to any preceding claim selected from the group consisting of:
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- [ (2 '-methyl [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -5- (3-benzyl-1, 2, 4-oxadiazol-5-yl) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (3- { [ (2-furylmethyl) sulfanyl ] -methyl } -1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ 2-oxo-2- (1-pyrrolidinyl) ethyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ (2-pyridylsulfanyl) methyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (4-fluorophenyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ (2-thienylsulfanyl) methyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [2- (3, 5-dimethyl-1H-pyrazol-1-yl) ethyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ (methylsulfonyl) methyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (5-methyl-3-isoxazolyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (2-thienylmethyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -Biphenyl ] -4-ylcarbonyl) -5- (3-phenyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (3- { [ (2-furylmethyl) sulfonyl ] -methyl } -1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -5- [3- (aminomethyl) -1, 2, 4-oxadiazol-5-yl ] -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- ([1, 1' -Biphenyl ] -4-ylcarbonyl) -5- {3- [ (RS) -hydroxy (phenyl) methyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ (1RS) -1-hydroxypropyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (hydroxymethyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-methyloxime
(3EZ, 5) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ (1S, 2R) -2-hydroxycyclohexyl ] -1, 2, 4-oxadiazol-5-yl } -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- [ (1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (4-piperidinyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- {3- [ (3RS) -piperidinyl ] -1, 2, 4-oxadiazol-5-yl } 3-pyrrolidinone O-carboxim-ine
(3EZ, 5S) -1- ([1, 1-Biphenyl ] -4-ylcarbonyl) -5- {3- [ (2RS) -piperidinyl ] -1, 2, 4-oxadiazol-5-yl } 3-pyrrolidinone O-carboxim-ine
(3EZ, 5S) -1- [ (2 '-chloro [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methoxime
(3EZ, 5S) -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -1- { [2 '- (trifluoromethyl) [1, 1' -biphenyl ] -4-yl ] -carbonyl } -3-pyrrolidinone O-methoxime
(3Z, 5S) -1- [ (2 '-fluoro [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- [ (4 '-fluoro [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methoxime
(3E, 5S) -1- [ (2 '-fluoro [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl
(3E, 5S) -1- [ (2 '-methyl [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl
(3Z, 5S) -1- [ (2 '-methyl [1, 1' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -5- [3- (1-acetyl-4-piperidinyl) -1, 2, 4-oxadiazol-5-yl ] -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -3-pyrrolidinone O-methoxime
(3Z, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-carboximidoyl
(3Z, 5S) -1- [ (2 ' -chloro-4 ' -fluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methoxime
(3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (1-methyl-4-piperidinyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-methoxime
5- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -N- [3 (dimethylamino) propyl ] -1, 2, 4-oxadiazole-3-carboxamide
5- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazole-3-carboxylic acid ethyl ester
(3E, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-carboximidoyl
(3Z, 5RS) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-carboximidoyl
(3EZ, 5S) -1- [ (2 ' -chloro-4 ' -fluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- [3- (2-hydroxyethyl) -1, 2, 4-oxadiazol-5-yl ] -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- [ (4 ' -fluoro-2 ' -methyl [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methoxime
2- {5- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4 oxadiazol-3-yl } ethyl [ (tert-butoxycarbonyl) amino ] -acetate
(3EZ, 5S) -1- [ (2 ' -chloro-4 ' -fluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methoxime
4- {5- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-3-yl } -1-piperidinecarboxylic acid tert-butyl ester
2- {5- [ (2S, 4EZ) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl ] -1, 2, 4-oxadiazol-3-yl } ethylamino acetate
(3E, 5S) -1- [ (2 ', 4 ' -difluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime
(3EZ, 5S) -1- [ (2 ', 4 ' -difluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime
4- { [ (2S, 4EZ) -2- (5- { (1S) -2-tert-butoxy-1- [ (tert-butoxycarbonyl) amino ] -ethyl } -1, 2, 4-oxadiazol-3-yl) -4- (methoxyimino) pyrrolidinyl ] -carbonyl } -1, 1 '-biphenyl (3EZ, 5S) -1- ([1, 1' -biphenyl ] -4-ylcarbonyl) -5- (5-vinyl-1, 2, 4-oxadiazol-3-yl) -3-pyrrolidinone O-methyloxime
(3Z, 5S) -1- [ (2 ', 4 ' -difluoro [1, 1 ' -biphenyl ] -4-yl) carbonyl ] -5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime.
11. Use of a pyrrolidine oxadiazole derivative according to any of claims 1-10 for the manufacture of a medicament for the treatment and/or prevention of preterm labor, premature birth and dysmenorrhea.
12. Use of a pyrrolidine oxadiazole derivative according to any of claims 1-10 for the preparation of a pharmaceutical composition for modulating an oxytocin receptor.
13. Use according to claim 12 wherein said modulation comprises blocking of the oxytocin receptor or antagonising the binding of oxytocin to its receptor.
14. Use according to claim 13 for the treatment or prevention of a disease mediated by the oxytocin receptor.
15. Use of a pyrrolidine oxadiazole derivative according to any of claims 1-10 for the preparation of an oral pharmaceutical composition.
16. A pharmaceutical composition comprising at least one pyrrolidine oxadiazole derivative according to any of claims 1-10 and a pharmaceutically acceptable carrier, diluent, or excipient thereof.
17. A process for the preparation of pyrrolidine oxadiazole compounds of general formula (I) wherein B is 1, 2, 4-oxadiazolyl of general formula (IIa) comprising the steps of:
diisopropylcarbodiimide as a coupling agent was added to the reaction mixture, and the reaction was carried out at room temperature with stirring overnight.
HK05108106.9A 2001-06-18 2002-06-14 Pyrrolidine oxadiazole-and thiadiazole derivatives HK1074204B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP01113632 2001-06-18
EP01113632.2 2001-06-18
PCT/EP2002/006629 WO2002102799A2 (en) 2001-06-18 2002-06-14 Pyrrolidine oxadiazole- and thiadiazole oxime derivatives being oxytocin receptor antagonists

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HK1074204A1 HK1074204A1 (en) 2005-11-04
HK1074204B true HK1074204B (en) 2010-05-20

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