TW201427938A - Preparation of GGA and derivatives thereof and their co-crystallization with urea or thiourea - Google Patents

Abstract

Provided herein are compositions comprising co-crystals of GGA or a GGA derivative (including salts and tauotomers thereof) with urea or thiourea, and processes related to such co-crystals. Also provided herein are methods, compounds, and compositions related to preparing trans GGA and derivatives thereof, and intermediates thereto.

Description

Preparation of geranylgeranylacetone (GGA) and its derivatives and their co-crystallization with urea or thiourea

The present invention provides compositions comprising co-crystals or coprecipitates of geranylgeranylacetone (GGA) or GGA derivatives (including salts and tautomers thereof) and urea or thiourea. Preferably, such co-crystals or co-precipitates are compared to the relative amounts of trans isomers in the mixture of cis and trans isomers used to prepare such co-crystallized GGA or GGA derivatives. Enrichment of all-trans isomers of GGA or GGA derivatives. The invention also relates to a simple method for isolating substantially pure cis and trans (preferably trans) GGA and GGA derivatives from a corresponding mixture of cis and trans isomers. Furthermore, the invention relates to the preparation of trans GGA and its derivatives, and their intermediates.

GGA has the following formula: It has been reported to have neuroprotective and related effects. See, for example, PCT Patent Application Publication No. WO 2012/031028, WO/2013/052148, WO/2013/130648, WO/2013/130242, and WO/2013/130654, the entire contents of each of which are incorporated herein by reference. . Surprisingly, all-trans (or 5E, 9E, 13E) GGA is more effective as a neuroprotective agent than 5-cis (or 5Z, 9E, 13E) GGA. However, conventional synthetic methods of GGA or GGA derivatives can provide a mixture of cis and trans isomers of GGA or GGA derivatives, such as 5E and 5Z isomers, which are difficult to separate (if It is not impossible to separate), especially on a scale suitable for large-scale manufacturing. In addition, methods for isolating isomers and compounds or compositions should be robust and reproducible to repeatedly provide compounds and compositions having the same or substantially the same specifications as required by the regulated pharmaceutical industry.

In certain aspects, the present invention provides compositions comprising co-crystals or coprecipitates of GGA or GGA derivatives, including their salts and tautomers, with urea and/or thiourea, and This type of co-crystal related manufacturing method. Preferably, the co-crystals comprise substantially all of the all-trans (hereinafter referred to as "trans") forms or substantially only the GGA or GGA derivatives of the trans form. In the context of the cis/trans configuration, used in this article By "substantially" is meant a desired configuration having at least 80%, more preferably at least 90%, even more preferably at least 95%, and most preferably at least 99%. The co-crystal may comprise at least 80%, more preferably at least 90%, even more preferably at least 95% and most preferably at least 99% of the trans isomer.

Without being bound by theory, urea and thiourea in a solid state form channels which are shaped to better accommodate the trans isomer of the GGA or GGA derivative rather than the corresponding cis isomer. Thus, when a mixture of trans and cis isomers of a GGA or GGA derivative is co-crystallized with urea or thiourea, the trans isomer of the GGA and GGA derivatives can be selectively erroneous in these channels. And/or isomerized from the cis isomer and provides a higher relative amount of trans isomer in the cocrystal compared to the relative amount of the trans isomer in the starting mixture (more than the corresponding Cis isomer).

In a related aspect, the invention also provides at least 80%, more preferably at least 90%, even more preferably at least 95%, most preferably at least 99% of the trans isomer of the GGA or GGA derivative.

In certain important constituent aspects, the invention relates to the co-crystallization of GGA and the following GGA derivatives, which are GGA intermediates, with urea or thiourea: When bromide is employed, urea can be a preferred crystallization agent. In certain embodiments wherein the co-crystal comprises GGA, at least 90%, more preferably at least 95%, even more preferably at least 99%, and most preferably at least 99.5% of the GGA or GGA derivatives are The form of the isomer exists. In these aspects, in a preferred embodiment, the co-crystal comprises thiourea as a channeling agent.

In another aspect of the invention, provided herein is a co-crystal or co-precipitate comprising a GGA or GGA derivative, and urea and/or thiourea, wherein the GGA salty GGA derivative is at least 80%, or at least 90%, Or at least 95%, or at least 99%, is present as a trans isomer. In one embodiment, the co-crystal or co-precipitate of the present invention provided herein is mixed with a composition comprising a GGA or GGA derivative, wherein the GGA or GGA derivative in the composition cooperates with the error. The GGA or GGA derivative, which is part of the co-crystal or co-precipitate, is substantially less present in trans form. In another embodiment, the co-crystal or co-precipitate provided herein is crystalline.

In another aspect, the text provides a trans form or substance A crystalline GGA derivative present in trans form.

The invention also provides for the preparation of GGA or GGA derivatives Co-crystallisation, and for the preparation of GGA or GGA derivatives containing at least 80%, more preferably at least 90%, even more preferably at least 95%, and most preferably at least 99% of the trans isomer of GGA or GGA derivatives The method of things.

In certain important method embodiments, the present invention provides methods for preparing GGA and co-crystals of the following GGA derivatives with urea or thiourea: It comprises contacting GGA or a GGA derivative as described above with urea or thiourea to provide co-crystallization of the GGA or GGA derivative with urea or thiourea. In certain embodiments, such co-crystals contain at least 90%, more preferably at least 95%, even more preferably at least 99%, most preferably at least 99.5% of the trans-isomeric forms of GGA or GGA derivatives. .

In certain preferred embodiments, the contacting is carried out in a solvent. In certain other embodiments, such as when the GGA or GGA derivative is present in a liquid state, such a liquid (substantially free of solvent) can be contacted with a solid urea or thiourea. Preferably, the GGA or GGA derivative is contacted with the urea or thiourea at a molar ratio of about 1:1. Excessive use, A urea or thiourea such as 50, 100 or 150 moles is used to drive the co-crystal formation. Urea or thiourea of less than 1 mole equivalent can also be used. The formation of co-crystals can be monitored, for example, by analyzing the cis/trans content of the reaction solution using HPLC. Other methods for misaligning other compounds are well known in the art and can be adapted to prepare the co-crystals of the present invention by those skilled in the art in view of the present disclosure.

In another aspect of the invention, the invention provides a process for the preparation of a GGA or GGA derivative wherein at least 80%, more preferably at least 90%, even more preferably at least 95%, and most preferably at least 99% The GGA or GGA derivative is present in the form of a trans isomer comprising co-crystals of GGA or GGA derivatives with urea or thiourea (at least 80%, more preferably at least 90%, even more preferably At least 95%, and optimally at least 99% of the GGA is present as a trans isomer) isolating the GGA or GGA derivative.

In certain important method embodiments, the invention provides methods for preparing GGA or the following GGA derivatives: At least 90%, more preferably at least 95%, even more preferably at least 99%, and most preferably at least 99.5% of the GGA or GGA derivative is present as a trans isomer, the method comprising from GGA or Co-crystallisation of a GGA derivative with urea or thiourea (at least 90%, more preferably at least 95%, even more preferably at least 99%, and most preferably at least 99.5% of GGA or GGA derivatives are trans-formed) The form of the construct exists) to isolate the GGA or GGA derivative. In any of the embodiments described, each of R ₂₀₁ and R _{203 is} independently hydrogen or C ₁ -C ₆ alkyl.

For the isolation, the co-crystal may be decomposed by a solvent such as water, and extracted with a solvent in which GGA is dissolved, but urea or thiourea is insoluble therein. Alternatively, in the case of a solid GGA derivative, the derivative may be insoluble therein, or a solvent (such as methanol) substantially insoluble therein decomposes the co-crystal, and the precipitated solid GGA derivative is isolated by filtration. Those skilled in the art will be able to adapt other isolation methods well known in the art to the isolation of GGA and GGA derivatives from their corresponding co-crystals provided herein in view of the present disclosure.

In one aspect of the method, provided herein are methods for preparing a co-crystal or coprecipitate of a GGA or GGA derivative with urea and/or thiourea, wherein at least 80%, or at least 90%, or at least 95%, or At least 99% of the GGA or GGA derivatives are present in the form of a trans isomer comprising cis and trans isomerism of the GGA or GGA derivative under conditions sufficient to form a co-crystal or coprecipitate a mixture of bodies in which the percentage of trans isomers in the mixture is less than the percentage in the mis-complexed co-crystals is contacted with a composition comprising urea and/or thiourea to provide co-crystals or Coprecipitate. In one embodiment, the method further comprises isolating the GGA or GGA derivative from the co-crystal to provide a GGA having at least 80%, or at least 90%, or at least 95%, or at least 99% of the trans isomer. Or GGA derivatives.

In another aspect, provided herein is a method of isolating a GGA or GGA derivative present in trans or substantially in trans form, the method comprising containing a GGA or GGA derivative and urea and/or thiourea a co-crystal or co-precipitate (wherein the GGA or GGA derivative mismatched in the co-crystal or co-precipitate is present in trans or substantially in trans form) and selectively dissolves the GGA or GGA The derivative, or the solvent of urea and/or thiourea is contacted under conditions sufficient for the dissolution. The purity of the GGA or GGA derivative thus dissolved and isolated can be determined by various methods including by HPLC. The isolated GGA or GGA derivative may be washed via a solvent which selectively dissolves urea or thiourea but does not dissolve the GGA or GGA derivative, or selectively dissolves the GGA or GGA derivative, but does not dissolve the urea or Solvent extraction of thiourea for further purification.

While the present disclosure is particularly relevant to urea and thiourea, those skilled in the art will be well aware that alkylation and other derivatives of urea and thiourea known to form channels similar to urea and thiourea can also be considered for use. In the present invention.

In various aspects, methods for the synthesis of GGA and its derivatives, and their intermediates are provided herein.

In one aspect, a method for preparing a compound of formula (XXXI) is provided: The method comprises: hydrolyzing a compound of formula (XXXII): Wherein: X ³⁰ and Y ³⁰ are each independently OR ³⁶ , SR ³⁶ , or X ³⁰ and Y ³⁰ together with the carbon atom to which they are attached form a ring of the formula: Wherein each R ³⁶ is independently C ₁ -C ₆ alkyl, each X ³¹ and X ³² are independently O or S; q is 1 or 2; each X ³³ is independently C ₁ -C ₆ alkyl; t is 0, 1, 2 or 3, and each R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ are independently H or C ₁ -C ₆ alkyl, or R ³¹ and R ³² together with the carbon atom to which they are attached A C ₅ -C ₆ cycloalkyl group optionally substituted with 1-3 C ₁ -C ₆ alkyl groups is formed.

In a further aspect, a method for preparing a compound of formula (XXXII) is provided: The method comprises: formulating a compound of formula (XXXIII): Wherein: the definition of the variable is as defined in the above formula (XXXII), and is contacted with a compound of the formula below under conditions suitable for the olefination of a compound of the formula (XXXIII) to produce a compound of the formula (XXXII): Wherein L ³⁰ is P(R ^Z ) ₃ , P(O)(R ^Z ) ₂ , SO ₂ R ^Z , Si(R ^Z ) ₃ , preferably P(R ^Z ) ₃ ; wherein R ^Z is C ₁ - C ₆ alkyl or aryl.

In a further aspect, a method for preparing a compound of formula (YXI) is provided: Wherein R ^{37 is} as defined above for R ³³ , R ³⁴ or R ³⁵ and n is 0-4 or 1-4, the method comprising: oxidizing a compound of formula (YXII):

In a further aspect, a method for preparing a compound of formula (YXII) is provided: The method comprises: reducing a compound of the formula (YXIII) Wherein R ³⁰ is a C ₁ -C ₆ alkyl group.

In a further aspect, a method for preparing a compound of formula (YXIII) is provided: The method comprises: contacting a proacetate of the formula CH ₃ -C(OR ³⁰ ) ₃ (wherein R ³⁰ is a C ₁ -C ₆ alkyl group) with a compound of the formula (YXIV):

In a further aspect, a method for preparing a compound of formula (YXIV) is provided: The method comprises: formulating a compound of the formula (YXV) And contact.

In each of the above examples, X ³⁰ and Y ^{30 have} the same meanings as defined in the above formula (XXXII), R ³⁷ is independently H or C ₁ -C ₆ alkyl, n is 1-5, and R ³⁰ is hydrogen. Or a C ₁ -C ₆ alkyl group, preferably an alkyl group.

Detailed description of the invention definition

The present invention relates to compositions of GGA and GGA derivatives co-crystallized with urea or thiourea, and methods for their preparation. The following terms will be defined before the detailed description of the invention.

It must be noted that the singular forms "a", "an", and "the" Thus, for example, reference to "solvent" includes several such solvents.

The term "comprising" or "comprises" as used herein is intended to mean that the compositions and methods include the recited elements, but do not exclude others. When used to define a composition and method, "consisting essentially of" shall mean that it does not include any element that has any substantial meaning to the combination for the stated purpose and, therefore, substantially as defined herein. The compositions or methods consisting of the elements will not include other substances or steps that do not materially affect the basic and novel characteristics of the claimed invention. "Consisting of" shall mean not including other ingredients in excess of trace elements and a number of method steps. Embodiments defined by each of these transition terms are within the scope of the invention.

Unless otherwise indicated, it is to be understood that the number of all the indicated components, the reaction conditions, and the like used in the specification and claims of the invention may be modified by the term "about" in all cases. Therefore, unless otherwise stated, the numerical parameters set forth in the following patent specification and the appended claims are approximation. The numerical parameters should be interpreted at least based on the number of meaningful numbers reported and the usual rounding techniques applied. When used for counting instructions (such as temperature, time, quantity, and concentration), including the range before In the meantime, the term "about" means an approximation that may vary by (+) or (-) 10%, 5%, or 1%.

C _m -C _n (such as C ₁ -C ₁₀ , C ₁ -C ₆ or C ₁ -C ₄ ) as used herein, when used in front of a group, refers to a group containing m to n carbon atoms. .

Geranylgeranylacetone (GGA) refers to a compound of the formula:

The composition comprising the compound is a mixture of geometric isomers of the compound.

The 5-trans isomer system of geranylgeranylacetone refers to a compound of the formula:

Wherein the No. 5 carbon atom is in the 5-trans (5E) configuration.

The 5-cis isomer system of geranylgeranylacetone refers to a compound of the formula: Wherein the No. 5 carbon atom is in the 5-cis (5Z) configuration.

The term "alkoxy" refers to to -O-alkyl.

The term "alkyl" refers to having from 1 to 10 carbon atoms (ie, C ₁ -C ₁₀ alkyl), or from 1 to 6 carbon atoms (ie, C ₁ -C ₆ alkyl), or from 1 to 4 The monovalent saturated aliphatic hydrocarbon group of a carbon atom. For example, the term includes both straight-chain and branched hydrocarbon groups such as methyl (CH ₃ -), ethyl (CH ₃ CH ₂ -), n-propyl (CH ₃ CH ₂ CH ₂ -), isopropyl Base ((CH ₃ ) ₂ CH-), n-butyl (CH ₃ CH ₂ CH ₂ CH ₂ -), isobutyl ((CH ₃ ) ₂ CHCH ₂ -), second butyl ((CH ₃ ) ( CH ₃ CH ₂ )CH-), tert-butyl ((CH ₃ ) ₃ C-), n-pentyl (CH ₃ CH ₂ CH ₂ CH ₂ CH ₂ -), and neopentyl ((CH ₃ )CCH ₂ -).

The term "aryl" refers to a monovalent, aromatic monocyclic or bicyclic ring having from 6 to 10 ring carbon atoms. Examples of the aryl group include a phenyl group and a naphthyl group. The ring of condensation may or may not be aromatic, with the proviso that the point of attachment is at the aromatic carbon atom. For example, but not limited to, the following is an aryl group:

The term "-CO ₂ H ester" refers to an ester formed between a -CO ₂ H group and an alcohol, preferably an aliphatic alcohol. Preferred examples include -CO ₂ R ^E wherein R ^E is an alkyl or aryl group optionally substituted with an amine group.

"Co-crystallized" or sometimes referred to herein as "coprecipitate" refers to a solid comprising a GGA or GGA derivative and a urea or thiourea, preferably a crystalline solid, preferably wherein the GGA or GGA is derived. Store Within the urea or thiourea crystal lattice, such as channels formed by urea or thiourea.

By "mismatched" is meant a GGA or GGA derivative that is bound by some quantifiable intermolecular force, non-limiting examples of which include hydrogen bonding and Van-Deval interaction, but also by entropy effect Combine.

The term "for the palm part" refers to the part of the palm of the hand. Such parts may have one or more asymmetric centers. Preferably, the pair of palmitic moieties are enantiomerically enriched, more preferably a single enantiomer. Non-limiting examples of palmar moieties include palmitic carboxylic acids, palmitic amines, palmitic amino acids (such as naturally occurring amino acids), palmitic alcohols, including palmitic steroids, etc. .

The term "cycloalkyl" refers to a monovalent, preferably saturated, hydrocarbyl mono-, di- or tricyclic ring having from 3 to 12 ring carbon atoms. Although a cycloalkyl group as used herein is preferably a saturated hydrocarbyl ring, it also includes a ring containing 1-2 carbon-carbon double bonds. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like. The condensed ring may or may not be a non-aromatic hydrocarbon ring, provided that the point of attachment is at the cycloalkyl carbon atom. For example, but not limited to, the following are monoalkyl groups:

The term "halogen" means fluoro, chloro, bromo and/or iodo.

The term "heteroaryl" refers to having from 2 to 14 ring carbon atoms and from 1 to 6 ring heteroatoms (preferably, selected from the group consisting of nitrogen, oxygen, sulfur, and phosphorus, and oxidized forms of nitrogen, sulfur, and phosphorus). A mono-, di- or tricyclic ring, with the proviso that the ring contains at least 5 ring atoms. Non-limiting examples of heteroaryl groups include furan, imidazole, oxadiazole, oxazole, pyridine, quinoline, and the like. The ring of condensation may or may not be an aromatic ring containing a hetero atom, provided that the point of attachment is a hetero atom. For example, but not limited to, the following is a heteroaryl group:

The term "heterocyclyl" or heterocyclic refers to 2-10 ring carbon atoms and 1-6 ring heteroatoms (preferably, selected from the group consisting of nitrogen, oxygen, sulfur, and phosphorus, and oxidized forms of nitrogen, Non-aromatic, mono-, di- or tricyclic rings of sulfur and phosphorus, with the proviso that the ring contains at least 3 ring atoms. While a heterocyclic group is preferably meant to refer to a saturated ring system, it also includes ring systems containing from one to three double bonds, with the proviso that these rings are non-aromatic. Non-limiting examples of heterocyclic groups include azalides, oxazolines, hexahydropyridyls, hexahydropyridyl Base, pyrrolidinyl, tetrahydrofuranyl and tetrahydropyranyl. The ring of condensation may or may not contain a ring containing a non-aromatic hetero atom, provided that the point of attachment is a heteroaryl group. For example, but not limited to, the following is a heterocyclic group:

The term "hydrolysis" refers to the splitting of R ^H -O-CO-, R ^H -O-CS- or R ^H -O-SO ₂ - into R ^H -OH, preferably by addition of water through a cleavable bond. Hydrolysis is carried out using a variety of methods well known to those skilled in the art, non-limiting examples of which include acidic hydrolysis and alkaline hydrolysis. Non-limiting examples of hydrolysis include hydrolysis of a ketal, a thioketal, and the like to the corresponding ketone. Hydrolysis is carried out using a variety of methods well known to those skilled in the art, non-limiting examples of which include acidic hydrolysis. There are various acids that can be used for hydrolysis, such as protic acid and Lewis acid.

The term "oxidizing" or "oxidation" refers to the removal of one or more electrons from a bond or atom, preferably by removing two electrons from a bond or atom. Non-limiting examples of oxidation include the conversion of an alcohol to an aldehyde.

The term "oxy" refers to a C=O group and a C=O group to replace two pairs of hydrogen atoms.

The term "alkenylation" refers to the conversion of a bond to the corresponding olefin derivative. For example, but not limited to, converting C=O to C=CR ^x R ^y , wherein R ^x and R ^y are alkyl groups.

The term "pharmaceutically acceptable" means safe and non-toxic to administration to the body (preferably, the human body).

The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt.

The term "reducing" or "reduction" refers to the addition of one or more electrons through a bond or atom, preferably by the addition of two electrons to a bond or atom. Non-limiting examples of reduction include carboxylic acid or Its ester is converted to an alcohol.

The term "salt" refers to an ionic compound formed between an acid and a base. When the compounds provided herein contain acidic functionalities, such salts include, but are not limited to, alkali metals, alkaline earth metals, and ammonium salts. Ammonium salts as used herein include salts containing a protonated nitrogen base and an alkylated nitrogen base. Exemplary and non-limiting cations useful as pharmaceutically acceptable salts include sodium, potassium, rubidium, cesium, ammonium, calcium, strontium, imidazolium and ammonium cations based on naturally occurring amino acids. When the compounds used herein contain a basic function, such salts include, but are not limited to, salts of organic acids such as carboxylic acids and sulfonic acids, and mineral acids such as hydrogen halides, sulfuric acid, phosphoric acid, and the like. Exemplary and non-limiting anions useful in pharmaceutically acceptable salts include oxalates, maleates, acetates, propionates, succinates, tartrates, chlorides, sulfates, hydrogen sulfates, Mono-, di- and tribasic phosphates, mesylate, tosylate, and the like.

The term "substantially pure trans isomer" means that 95%, preferably 96%, more preferably 99%, and even more preferably 99.5% or more of the molar amount is trans isomerism. The remainder is the trans isomer of the corresponding cis isomer.

In the context of GGA and GGA derivatives, "trans" refers to the GGA scaffold as shown below: Wherein R ¹ -R ⁵ are defined herein and q is 0-2. As shown, each double bond is in the trans or E configuration. Conversely, the cis form of a GGA or GGA derivative will contain one or more such bonds in the cis or Z configuration.

GGA derivative

The GGA derivatives which can be used in the present invention include those described in U.S. Patent Application Serial No. 13/815,831, U.S. Patent Application Publication No. US 2006/0052347, U.S. Patent No. 5,453,524, PCT Publication No. WO 2012/026813, WO The entire contents of each of which is incorporated herein by reference in its entirety by reference in its entirety in the the the the the the the the the the the the the the the the the the the The structures of these and other GGA derivatives as used herein are shown below.

In one aspect, the GGA derivative used herein is a compound of formula I: Wherein n is 1 or 2; each of R ¹ and R ² is independently H or C ₁ -C ₆ alkyl, or R ¹ and R ² are taken together with the carbon atom to which they are attached, optionally 1-3 C ₁ - a substituted alkyl group of C ₆ C ₅ -C ₇ cycloalkyl ring; each R ^3, R ⁴ and R ⁵ are independently hydrogen or lines C ₁ -C ₆ alkyl; Q ¹ is - (C = O) -, -(C=S)-, or -S(O ₂ )-; Q ₂ is hydrogen, R ⁶ , -OR ⁶ , -NR ⁷ R ⁸ , or a palmitic moiety; R ⁶ is: C ₁ -C _{a 6} alkyl group which may be optionally substituted with a substituent of the following group: -CO ₂ H or its ester, C ₁ -C ₆ alkoxy group, oxy group, -CR=CR ₂ , -C≡CR, C ₃ a C ₈ cycloalkyl group, a C ₃ -C ₈ heterocyclic group, a C ₆ -C ₁₀ aryl group, or a C ₂ -C ₁₀ heteroaryl group, wherein each R is independently hydrogen or a C ₁ -C ₆ alkyl group; ₃ -C ₁₀ cycloalkyl; C ₃ -C ₈ heterocyclyl; C ₆ -C ₁₀ aryl; or C ₂ -C ₁₀ heteroaryl; wherein each cycloalkyl, heterocyclyl, aryl or heteroaryl The group may be optionally substituted with 1-3 alkyl groups, optionally substituted with 1-3 halogen (preferably fluorine) groups, or R ¹⁸ and R ¹⁹ together with the nitrogen atom to which they are attached form a 5-7 member. a ring; each of R ⁷ and R ⁸ is independently hydrogen or as defined for R ⁶ ; Means a mixture of cis and trans isomers at corresponding positions, wherein at least 80%, preferably no more than 95%, of the compound of formula (I) is present as a trans isomer; Salt or tautomer.

In one embodiment, the GGA derivative used is of formula (IA):

It is a substantially pure trans isomer surrounding a 2,3 double bond, wherein n, R ¹ -R ⁵ , Q ¹ and Q ^{2 are} as defined in the above formula (I).

In another embodiment, n is one. In another embodiment, n is 2.

In another embodiment, the GGA derivative used is of formula (IB): It is a substantially pure trans isomer of a 2,3 double bond, wherein R ¹ -R ⁵ , Q ¹ and Q ^{2 are} as defined in the above formula (I).

In another embodiment, the GGA derivative used is Formula II:

Wherein Q ¹ and Q ^{2 are} as defined in the above formula (I).

In another embodiment, the GGA derivative used is a compound of (II-A), (II-B), or (II-C):

Wherein R ^{6 -} R ^{8 are} as defined in the above formula (I).

In another embodiment, the GGA derivative used is a compound of formula (II-D), (II-E), or (II-F):

It is a substantially pure trans isomer surrounding a 2,3 double bond, wherein R ⁶ -R ^{8 are} as defined in the above formula (I).

In a preferred embodiment, R ⁶ is a C ₆ -C ₁₀ aryl group such as a naphthyl group. In another preferred embodiment, R ⁶ is a heteroaryl group such as a quinolinyl group.

In another aspect, the GGA derivative used in the present invention is of formula (II): Or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1; n is 0, 1, or 2; each of R ¹ and R ² is independently C ₁ -C ₆ alkyl, or R ¹ and R ^{2 are the} same The linked carbon atoms together form a C ₅ -C ₇ cycloalkyl ring optionally substituted with 1-3 C ₁ -C ₆ alkyl groups; each R ³ , R ⁴ and R ⁵ is independently hydrogen or C ₁ - C ₆ alkyl; Q is -X-CO-NR ¹⁸ R ¹⁹ , -X-CS-NR ¹⁸ R ¹⁹ , or -X-SO ₂ -NR ¹⁸ R ¹⁹ ; X is -O-, -S-, - NR ⁷ -, or -CR ⁸ R ⁹ ; R ⁷ is hydrogen, or together with R ¹⁸ or R ¹⁹ and the inserted atoms form a 5-7 member which can be optionally substituted with 1-3 C ₁ -C ₆ alkyl groups. a heterocyclic ring; each of R ⁸ and R ⁹ is independently hydrogen, C ₁ -C ₆ alkyl, -COR ⁸¹ or -CO ₂ R ⁸¹ , or R ^{8 is} formed freely with R ¹⁸ or R ¹⁹ and the inserted atom. a 5-7 heterocyclyl ring substituted with 1-3 C ₁ -C ₆ alkyl groups; and each R ¹⁸ and R ¹⁹ is independently hydrogen; C ₁ -C ₆ alkyl, optionally via the following group Substituted substituents: -CO ₂ H or its ester, C ₁ -C ₆ alkoxy, oxy, -CR=CR ₂ , -CCR, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ a cyclic group, a C ₆ -C ₁₀ aryl group, or a C ₂ -C ₁₀ heteroaryl group, wherein each R is independently hydrogen or a C ₁ -C ₆ alkyl group; ₃ -C ₁₀ cycloalkyl; C ₃ -C ₈ heterocyclyl; C ₆ -C ₁₀ aryl; or C ₂ -C ₁₀ heteroaryl; wherein each cycloalkyl, heterocyclyl, aryl or heteroaryl The group may be optionally substituted with 1-3 alkyl groups, optionally substituted with 1-3 halogen (preferably fluorine) groups, or R ¹⁸ and R ¹⁹ together with the nitrogen atom to which they are attached form a 5-7 member. ring.

The compounds of formula (II) as used herein include optical isomers such as enantiomers and diastereomers. And as the user herein, preferably, refers to a phenyl ester or a C ₁ -C ₆ alkyl, phenyl or alkyl which may be optionally substituted by the group.

In one embodiment, the compound of formula (II) is a compound of the formula: Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Q are as defined in any aspect or embodiment herein.

In another embodiment, the GGA derivative used is a compound of the formula: Wherein R ¹ , R ² , R ⁴ , R ⁵ and Q are as defined in any aspect or embodiment herein.

In one embodiment, the compound of formula (II) is a compound of the formula:

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Q are as defined in any aspect or embodiment herein.

In another embodiment, the GGA derivative used is a compound of the formula: Wherein R ¹ , R ² , R ⁴ , R ⁵ , m, n, X, R ¹⁸ and R ^{19 are} as defined in any aspect or embodiment herein.

In another embodiment, the GGA derivative used is a compound of the formula: Wherein R ¹ , R ² , R ⁴ , R ⁵ , m, n and R ^{18 are} as defined in any aspect or embodiment herein.

In another embodiment, the GGA derivative used is a compound of the formula:

Wherein R ¹⁸ is as defined in any aspect or embodiment herein.

In another embodiment, the GGA derivative used is a compound of the formula:

Wherein R ¹⁸ is as defined in any aspect or embodiment herein.

In another embodiment, the GGA derivative used is a compound of the formula: Wherein R ¹⁸ is as defined in any aspect or embodiment herein.

In another embodiment, the GGA derivative used is a compound of the formula:

Wherein R ¹⁸ is as defined in any aspect or embodiment herein.

In another embodiment, the GGA derivative used is a compound of the formula: Wherein the definition of R ¹⁸ and R ¹⁹ are as defined in any of the embodiments or aspects of the embodiments herein.

In another embodiment, the GGA derivative used is a compound of the formula: Wherein R ¹⁸ is as defined in any aspect or embodiment herein.

In another embodiment, the GGA derivative used is a compound of the formula:

Wherein R ¹⁸ and R ^{19 are} as defined in any aspect or embodiment herein.

In one embodiment, m is zero. In another embodiment, m is one.

In another embodiment, n is zero. In another embodiment, n is one. In another embodiment, n is 2.

In another embodiment, m+n is one. In another embodiment, m+n is 2. In another embodiment, m+n is 3.

In another embodiment, R ¹ and R ² are independently C ₁ -C ₆ alkyl. In another embodiment, R ¹ and R ² are independently methyl, ethyl or isopropyl.

In another embodiment, R ¹ and R ² together with the carbon atom to which they are attached form a C ₅ -C ₇ cycloalkyl ring optionally substituted with 1-3 C ₁ -C ₆ alkyl groups. In another embodiment, R ¹ and R ² together with the carbon atom to which they are attached form a ring as shown in the following figure:

In another embodiment, R ³ , R ⁴ and R ⁵ are independently C ₁ -C ₆ alkyl. In another embodiment, one of R ³ , R ⁴ and R ⁵ is an alkyl group and the balance is hydrogen. In another embodiment, two of R ³ , R ⁴ and R ⁵ are alkyl and the balance is hydrogen. In another embodiment, R ³ , R ⁴ and R ⁵ are hydrogen. In another embodiment, R ³ , R ⁴ and R ⁵ are methyl.

In another embodiment, Q is -X-CO-NR ¹⁸ R ¹⁹ . In another embodiment, Q is -X-CS-NR ¹⁸ R ¹⁹ . In another embodiment, Q is -X-SO ₂ -NR ¹⁸ R ¹⁹ . In another embodiment, Q is ^{-OCONHR 18, -OCONR 18 R 19,} -NHCONHR 18, -NHCONR 18 R 19, -OCSNHR 18, -OCSNR 18 R 19, -NHCSNHR 18, or -NHCSNR ¹⁸ R ^19.

In another embodiment, X is -O-. In another embodiment, X is -NR ⁷ -. In another embodiment, X is -CR ⁸ R ⁹ .

In another embodiment, one of R ¹⁸ and R ¹⁹ is hydrogen. In another embodiment, one or both of R ¹⁸ and R ¹⁹ are C ₁ -C ₆ alkyl. In another embodiment, one or both of R ¹⁸ and R ¹⁹ are C ₁ -C ₆ alkyl groups which are optionally substituted with an R ²⁰ group. In another embodiment, one or both of R ¹⁸ and R ¹⁹ are C ₃ -C ₁₀ cycloalkyl. In another embodiment, one or both of R ¹⁸ and R ¹⁹ are C ₃ -C ₁₀ cycloalkyl substituted with 1-3 alkyl groups. In another embodiment, one or both of R ¹⁸ and R ¹⁹ are C ₃ -C ₁₀ cycloalkyl. In another embodiment, one or both of R ¹⁸ and R ¹⁹ are C ₃ -C ₈ heterocyclyl. In another embodiment, one or both of R ¹⁸ and R ¹⁹ are C ₆ -C ₁₀ aryl. In another embodiment, one or both of R ¹⁸ and R ¹⁹ are C ₂ -C ₁₀ heteroaryl. In another embodiment, R ¹⁸ and R ¹⁹ together with the nitrogen atom to which they are attached form a 5-7 membered heterocyclic ring.

In another embodiment, R ²⁰ is -CO ₂ H or an ester thereof. In another embodiment, R ²⁰ is C ₃ -C ₈ . In another embodiment, R ²⁰ is cycloalkyl. In another embodiment, R ²⁰ is C ₃ -C ₈ heterocyclyl. In another embodiment, R ²⁰ is C ₆ -C ₁₀ aryl group. In another embodiment, R ²⁰ is C ₂ -C ₁₀ heteroaryl.

In another embodiment, examples of compounds useful in the present invention include certain compounds in the table below.

In another aspect, the GGA derivative used is a compound of the formula: Wherein m is 0 or 1; n is 0, 1 or 2; each of R ¹ and R ² is independently C ₁ -C ₆ alkyl, or R ¹ and R ² are taken together with the carbon atom to which they are attached, optionally - 3 C ₁ -C ₆ alkyl groups substituted C ₅ -C ₇ cycloalkyl rings; each R ³ , R ⁴ and R ⁵ are independently hydrogen or C ₁ -C ₆ alkyl; Q is -X- CO-NR ¹⁸ R ¹⁹ or -X-SO ₂ -NR ¹⁸ R ¹⁹ ; X is -O-, -NR ⁷ -, or -CR ⁸ R ⁹ ; R ⁷ is hydrogen or is inserted with R ¹⁸ or R ¹⁹ The atoms together form a 5-7 membered ring which is optionally substituted with 1-3 C ₁ -C ₆ alkyl groups; each R ⁸ and R ⁹ is independently hydrogen, C ₁ -C ₆ alkyl, -COR ⁸¹ or -CO ₂ R ⁸¹ , or R ⁸ together with R ¹⁸ or R ¹⁹ and the inserted atoms form a 5-7 membered cycloalkyl or heterocyclyl ring which may be optionally substituted with 1-3 C ₁ -C ₆ alkyl groups And each of R ¹⁸ and R ¹⁹ is independently hydrogen, C ₁ -C ₆ alkyl, which may be optionally substituted with a substituent of the following group: -CO ₂ H or its ester, C ₃ -C ₈ cycloalkyl, a C ₃ -C ₈ heterocyclic group, a C ₆ -C ₁₀ aryl group, or a C ₂ -C ₁₀ heteroaryl group, or a C ₃ -C ₁₀ cycloalkyl group, a C ₃ -C ₈ heterocyclic group, C ₆ -C ₁₀ aryl group, or a C ₂ -C ₁₀ heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl or heteroaryl groups may vary 1-3 substituted alkyl groups, or R ¹⁸ and R ¹⁹ together form a 5-7 membered heterocyclic ring with the nitrogen atom to which they are attached.

In another aspect, the GGA derivative used herein is a compound of formula III:

Wherein m is 0 or 1; n is 0, 1 or 2; each of R ¹ and R ² is independently C ₁ -C ₆ alkyl, or R ¹ and R ² are taken together with the carbon atom to which they are attached, optionally a C ₅ -C ₇ cycloalkyl ring substituted with 3 C ₁ -C ₆ alkyl groups; each R ³ , R ⁴ and R ⁵ is independently hydrogen or C ₁ -C ₆ alkyl; Q is selected from the following Group: When X is bonded via a single bond, X is -O-, -NR ⁷ -, or -CR ⁸ R ⁹ -, and when X is bonded via a double bond, X is -CR ⁸ -; Y ¹ is A hydrogen atom or -OR ¹⁰ , Y ² is -OR ¹¹ or -NHR ¹² , or Y ¹ and Y ² are bonded to form a oxy group (=O), an imido group (=NR ¹³ ), a thiol group (=N) -OR ¹⁴ ), or a substituted or unsubstituted vinyl group (=CR ¹⁶ R ¹⁷ ); R ⁶ is a C ₁ -C optionally substituted with 1-3 alkoxy groups or 1-5 halogen groups ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, C ₃ -C ₈ heterocyclic, or C ₂ - a C ₁₀ heteroaryl group, wherein each cycloalkyl or heterocyclic group is optionally substituted with 1-3 C ₁ -C ₆ alkyl groups, or wherein each aryl or heteroaryl group is independently 1-3 C ₁ -C ₆ alkyl or nitro group substituted, or R ⁶ is -NR ¹⁸ R ¹⁹ ; R ⁷ is hydrogen, or together with R ⁶ and the inserted atom, may be optionally passed through 1-3 C ₁ -C ₆ alkyl groups a 5-7 membered ring substituted; each R ⁸ and R ⁹ is independently hydrogen, C ₁ -C ₆ alkyl, -COR ⁸¹ or -CO ₂ R ⁸¹ , or R ^{8 is} formed together with R ⁶ and the inserted atom a 5-7 membered cycloalkyl or heterocyclyl ring optionally substituted with 1-3 C ₁ -C ₆ alkyl groups; R ¹⁰ is C ₁ -C ₆ alkyl; R ¹¹ and R ¹² are independently C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, -CO ₂ R ¹⁵ , or -CON(R ¹⁵ ) ₂ Or R ¹⁰ and R ¹¹ together with the inserted carbon atom form a heterocyclic ring which may be optionally substituted by 1 to 3 C ₁ -C ₆ alkyl groups; R ¹³ is a C ₁ -C ₆ alkyl group or may be optionally 1- 3 C ₁ -C ₆ alkyl group substituted C ₃ -C ₁₀ cycloalkyl; R ¹⁴ is hydrogen, C ₁ -C ₆ alkyl, which may be optionally substituted with the following group of substituents: -CO ₂ H Or an ester thereof, or a C ₆ -C ₁₀ aryl group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, a C ₃ -C ₁₀ cycloalkyl group, or a C ₃ -C ₈ heterocyclic group, each of which a cycloalkyl group, a heterocyclic group, or an aryl group may be optionally substituted with 1-3 alkyl groups; each R ¹⁵ group is independently hydrogen, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkyl, which may Optionally substituted with 1-3 substituents selected from the group consisting of: -CO ₂ H or its ester, aryl, or C ₃ -C ₈ heterocyclic group, or two R ¹⁵ groups bonded to the nitrogen The atoms together form a 5-7 membered heterocyclic ring; R ¹⁶ is hydrogen or C ₁ -C ₆ alkyl; R ¹⁷ is hydrogen, C ₁ -C ₆ alkyl substituted with 1-3 hydroxyl groups, -CHO, or -CO ₂ H or an ester; R ¹⁸ and R ¹⁹ are each independently hydrogen-based, C ₁ -C ₆ alkyl Which are free of by substituents from the group: -CO ₂ H or an ester, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₈ heterocyclyl, C ₆ -C ₁₀ aryl, or C ₂ a -C ₁₀ heteroaryl group, or a C ₃ -C ₁₀ cycloalkyl group, a C ₃ -C ₈ heterocyclic group, a C ₆ -C ₁₀ aryl group, or a C ₂ -C ₁₀ heteroaryl group, wherein each cycloalkyl group a heterocyclic group, an aryl group or a heteroaryl group may be optionally substituted with 1 to 3 alkyl groups, or R ¹⁸ and R ¹⁹ together with the nitrogen atom to which they are attached form a 5-7 membered heterocyclic ring; and each R ⁸¹ is independently It is a C ₁ -C ₆ alkyl group.

In one embodiment, m is zero. In another embodiment, m is one. In another embodiment, n is zero. In another embodiment, n is one. In another embodiment, n is 2.

In one embodiment, the compound of formula (III) is a compound of the formula: Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X, Y ¹ and Y ^{2 are} as defined in any aspect or embodiment herein.

In one embodiment, the GGA derivative used is a compound of the formula: Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X, Y ¹ and Y ^{2 are} as defined in any aspect or embodiment herein.

In another embodiment, the GGA derivative used is a compound of the formula: Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X and Y ^{2 are} as defined in any aspect or embodiment herein.

In another embodiment, the GGA derivative used is a compound of the formula: Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and X are as defined in any aspect or embodiment herein.

In another embodiment, the GGA derivative used is a compound of the formula: Wherein R ¹ , R ² , R ⁴ , R ⁵ and Q are as defined in any aspect or embodiment herein.

In another embodiment, the GGA derivative used is a compound of the formula: Wherein R ¹ , R ² , R ⁴ , R ⁵ , m, n, X and R ^{6 are} as defined in any aspect or embodiment herein.

In another embodiment, the GGA derivative used is a compound of the formula: Wherein R ¹ , R ² , R ⁴ , R ⁵ , m, n and R ^{18 are} as defined in any aspect or embodiment herein.

In another embodiment, the GGA derivative used is a compound of the formula: Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , m, n and R ^{15 are} as defined in any aspect or embodiment herein.

In another embodiment, each of R ¹ and R ² is C ₁ -C ₆ alkyl. In another embodiment, each of R ¹ and R ² is methyl, ethyl or isopropyl. In another embodiment, R ¹ and R ² together with the carbon atom to which they are attached form a 5-6 membered ring which is optionally substituted with 1-3 C ₁ -C ₆ alkyl groups. In another embodiment, R ¹ and R ² together with the carbon atom to which they are attached form a ring as shown in the following figure:

In another embodiment, R ³ , R ⁴ and R ⁵ are C ₁ -C ₆ alkyl. In another embodiment, one of R ³ , R ⁴ and R ⁵ is an alkyl group and the balance is hydrogen. In another embodiment, R ³ , R ⁴ and R ⁵ are both alkyl and the balance is hydrogen. In another embodiment, R ³ , R ⁴ and R ⁵ are hydrogen. In another embodiment, R ³ , R ⁴ and R ⁵ are methyl.

In another embodiment, X is O. In another embodiment, X is -NR ^7. In another embodiment, R ⁷ is hydrogen. In another embodiment, R ⁷ and R ⁶ together with the inserted atoms form a 5-7 membered ring which is optionally substituted with 1-3 C ₁ -C ₆ alkyl groups. In another embodiment, X is -CR ⁸ R ⁹ -. In another embodiment, X is -CR ⁸ -. In another embodiment, each of R ⁸ and R ⁹ is independently hydrogen, C ₁ -C ₆ alkyl, -COR ⁸¹ or -CO ₂ R ⁸¹ . In another embodiment, R ⁸ is hydrogen and R ⁹ is hydrogen, C ₁ -C ₆ alkyl, -COR ⁸¹ or -CO ₂ R ⁸¹ .

In another embodiment, R ⁹ is hydrogen. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is methyl. In another embodiment, R ⁹ is -CO ₂ R ⁸¹ . In another embodiment, R ⁹ is -COR ⁸¹ .

In another embodiment, R ⁸ and R ⁶ together with the inserted atoms form a 5-7 membered ring. In another embodiment, the portion: It is "Q" and has the following structure: Wherein R ⁹ is hydrogen, C ₁ -C ₆ alkyl or -CO ₂ R ⁸¹ and n is 1, 2 or 3. In these embodiments, in some embodiments, R ⁹ is hydrogen or C ₁ -C ₆ alkyl. In one embodiment, R ⁹ is hydrogen. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl.

In another embodiment, R ⁶ is C ₁ -C ₆ alkyl. In another embodiment, R ⁶ is methyl, ethyl, butyl, isopropyl or tert-butyl. In another embodiment, R ⁶ is C ₁ -C ₆ alkyl substituted with 1-3 alkoxy groups or 1-5 halo groups. Embodiment, R ⁶ is an alkyl group substituted with alkoxy groups in another embodiment. In another embodiment, R ⁶ is alkyl substituted with 1-5 (preferably 1-3) halogen (preferably fluoro) groups.

In another embodiment, R ⁶ is NR ¹⁸ R ¹⁹ . In a preferred embodiment, R ¹⁹ is H. In a preferred embodiment, R ¹⁸ is C ₁ -C ₆ alkyl. In a preferred embodiment, R ¹⁸ is C ₁ -C ₆ alkyl, which may be optionally substituted with the following group of substituents: -CO ₂ H or its ester, C ₃ -C ₁₀ cycloalkyl, C ₃ a -C ₈ heterocyclic group, a C ₆ -C ₁₀ aryl group, or a C ₂ -C ₁₀ heteroaryl group. In another preferred embodiment, R ¹⁸ is C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₈ heterocyclyl, C ₆ -C ₁₀ aryl, or C ₂ -C ₁₀ heteroaryl. In a more preferred embodiment, R ¹⁸ is C ₃ -C ₁₀ cycloalkyl.

In another embodiment, R ⁶ is C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl. In another embodiment, R ⁶ is C ₃ -C ₁₀ cycloalkyl. In another embodiment, R ⁶ is C ₃ -C ₁₀ cycloalkyl substituted with 1-3 C ₁ -C ₆ alkyl groups. Embodiment, R ⁶ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, or in another embodiment. In another embodiment, R ⁶ is C ₆ -C ₁₀ aryl or C ₂ -C ₁₀ heteroaryl. Embodiment, R ⁶ is a 5-7 membered containing at least one oxygen atom of the heteroaryl group to another embodiment. In another embodiment, R ⁶ is C ₆ -C ₁₀ aryl, C ₃ -C ₈ heterocyclyl or C ₂ -C ₁₀ heteroaryl, wherein each aryl, heterocyclyl or heteroaryl is Optionally substituted with 1-3 C ₁ -C ₆ alkyl groups.

In another embodiment, Y ² is -OR ¹¹ . In another embodiment, Y ¹ and Y ² are joined to form =NR ¹³ . In another embodiment, Y ¹ and Y ² are joined to form =NOR ¹⁴ . In another embodiment, Y ¹ and Y ² are joined to form (=O). In another embodiment, Y ¹ and Y ² are joined to form =CR ¹⁶ R ¹⁷ .

In another embodiment, Q is =CR ⁹ COR ⁶ . In another embodiment, R ⁶ is C ₁ -C ₆ alkyl optionally substituted by alkoxy. In another embodiment, R ⁶ is C ₃ -C ₈ cycloalkyl. In another embodiment, R ⁹ is hydrogen. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CO ₂ R ⁸¹ . In another embodiment, R ⁹ is COR ⁸¹ .

In another embodiment, Q is ^{_{CH 2 -CH (O-CONHR 15}} ) -R 6. In another embodiment, R ¹⁵ is C ₃ -C ₈ cycloalkyl. In another embodiment, R ¹⁵ is C ₁ -C ₁₅ alkyl, which may be optionally substituted with from 1 to 3 substituents selected from the group consisting of: -CO ₂ H or its ester, aryl, or C ₃ -C ₈ heterocyclic group. In a preferred embodiment of these embodiments, R ⁶ is C ₁ -C ₆ alkyl.

In another embodiment, Q is -O-CO-NHR ¹⁸ . Within these embodiments, in another embodiment, R ¹⁸ is C ₁ -C ₆ alkyl, which may be optionally substituted with the following group of substituents: -CO ₂ H or its ester, C ₃ -C ₈ A cycloalkyl group, a C ₃ -C ₈ heterocyclic group, a C ₂ -C ₁₀ aryl group or a C ₂ -C ₁₀ heteroaryl group. In still another embodiment, R ¹⁸ is C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ heterocyclyl, C ₂ -C ₁₀ aryl or C ₂ -C ₁₀ heteroaryl.

In another embodiment, R ¹⁴ is hydrogen. In another embodiment, R ¹⁴ is C ₁ -C ₆ alkyl optionally substituted by -CO ₂ H or an ester thereof, or C ₆ -C ₁₀ aryl optionally substituted with 1-3 alkyl groups . In another embodiment, R ¹⁴ is C ₂ -C ₆ alkenyl. In another embodiment, R ¹⁴ is C ₂ -C ₆ alkynyl. In another embodiment, R ¹⁴ is C ₃ -C ₆ cycloalkyl optionally substituted with 1-3 alkyl groups. In another embodiment, R ¹⁴ is a C ₃ -C ₈ heterocyclyl optionally substituted with 1-3 alkyl groups.

In another embodiment, preferably, R ¹⁶ is hydrogen. In another embodiment, R ¹⁷ is CO ₂ H or an ester thereof. In another embodiment, R ¹⁷ is substituted with 1-3 hydroxy groups of C ₁ -C ₆ alkyl. In another embodiment, R ¹⁷ is a substituted hydroxyl groups of a C ₁ -C ₃ alkyl. In another embodiment, R ¹⁷ is -CH ₂ OH.

In another embodiment, R ¹⁰ and R ¹¹ together with the inserted carbon and oxygen atoms form a heterocyclic ring of the formula:

Wherein q is 0 or 1, p is 0, 1, 2, or 3 and R ²⁰ is a C ₁ -C ₆ alkyl group.

In another embodiment, q is one. In another embodiment, q is 2. In another embodiment, p is zero. In another embodiment, p is one. In another embodiment, p is 2. In another embodiment, p is 3.

In another embodiment, examples of compounds useful in the present invention include certain compounds listed in the table below.

In one aspect, the GGA derivative is a compound of formula (IV): Or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1; n is 0, 1, or 2; each of R ¹ and R ² is independently C ₁ -C ₆ alkyl, or R ¹ and R ² together with the carbon atom to which they are attached form a C ₅ -C ₇ cycloalkyl ring optionally substituted with 1-3 C ₁ -C ₆ alkyl groups; each R ³ , R ⁴ and R ⁵ Independently hydrogen or C ₁ -C ₆ alkyl, or R ⁵ and Q together with the inserted carbon atom form a 6-membered aromatic ring, or a 5-8 membered cycloalkenyl ring, or a 5-14 membered heteroaryl or hetero a ring wherein each aryl, cycloalkenyl, heteroaryl, or heterocyclic ring is optionally substituted with 1-2 substituents selected from the group consisting of halogen, hydroxy, oxy, and -N (R ^{10 )} ₂ ) and C ₁ -C ₆ alkyl; Q is a 6-10 membered aryl group, or a 5-14 membered heteroaryl group, or a heterocyclic ring containing up to 6 ring heteroatoms, wherein the hetero atom is selected from the group consisting of Group: O, N, S, and N and S in oxidized form, further wherein the aryl, heteroaryl, or heterocyclyl ring is optionally substituted with 1-2 substituents selected from the group consisting of: a hydroxy, oxy, -N(R ¹⁰ ) ₂ and C ₁ -C ₆ alkyl group, wherein the alkyl group is optionally 1-3 selected from a hydroxyl group, NH ₂ , -CO ₂ H or Substituted by an ester or a guanamine, a substituent of a 5-9 membered heteroaryl group containing up to 3 ring heteroatoms, wherein the heteroaryl group is optionally passed through 1-3 hydroxy groups, -N(R ¹⁰ ) ₂ and C _{a 1-} C ₆ alkyl group, and a phenyl group (which may be optionally substituted with 1-3 substituents selected from the group consisting of C ₁ -C ₆ alkyl, hydroxy and halo groups); and wherein each R ¹⁰ Independently hydrogen or C ₁ -C ₆ alkyl.

Compounds of formula (IV) as used herein include tautomers and optical isomers such as enantiomers and diastereomers. Preferably, as used herein, ester means the phenyl or C ₁ -C ₆ alkyl, phenyl or alkyl group which may be optionally substituted by an amine group. Preferably, a guanamine as used herein refers to a moiety of the formula -CON(R ¹⁰ ) ₂ wherein R ¹⁰ is as defined above.

In some embodiments, the Q system is selected from the group consisting of oxazole, oxadiazole, oxazoline, azalide, imidazole, diazole, triazole, and thiazole, wherein each heteroaryl or heterocyclic group It is arbitrarily replaced by those disclosed above.

In one embodiment, the GGA derivative used is a compound of the formula:

In another embodiment, the GGA derivative used is a compound of the formula: Wherein R ¹ , R ² , R ⁴ , R ⁵ and Q are as defined in any aspect or embodiment herein.

In another embodiment, the Q system is selected from the group consisting of: Wherein R ¹¹ is as defined above. In another embodiment, Q is phenyl, which is optionally substituted as described herein. In another embodiment, Q is benzimidazole, benzoxazole, and such other 5-6 fused 9-membered bicyclic heteroaryl or heterocycle. In another embodiment, Q is quinoline, isoquinoline, and such other 6-6 fused 10-membered cycloheteroaryl or heterocycle. In another embodiment, Q is benzodiazepine Or a derivative thereof, such as benzodiazepine Ketone (benzodiazepinone). Those skilled in the art are familiar with various benzodiazepines. And its derivatives.

In another embodiment, m is zero. In another embodiment, m is one.

In another embodiment, n is zero. In another embodiment, n is 1. In another embodiment, n is 2.

In another embodiment, m+n is one. In another embodiment, m+n is 2. In another embodiment, m+n is 3.

In another embodiment, R ¹ and R ² are independently C ₁ -C ₆ alkyl. In another embodiment, R ¹ and R ² are independently methyl, ethyl or isopropyl.

In another embodiment, R ¹ and R ² together with the carbon atom to which they are attached form a C ₅ -C ₇ cycloalkyl ring optionally substituted with 1-3 C ₁ -C ₆ alkyl groups. In another embodiment, R ¹ and R ² together with the carbon atom to which they are attached form a ring as shown in the following figure:

In another embodiment, R ³ , R ⁴ and R ⁵ are independently C ₁ -C ₆ alkyl. In another embodiment, one of R ³ , R ⁴ and R ⁵ is an alkyl group and the balance is hydrogen. In another embodiment, R ³ , R ⁴ and R ⁵ are both alkyl and the balance is hydrogen. In another embodiment, R ³ , R ⁴ and R ⁵ are hydrogen. In another embodiment, R ³ , R ⁴ and R ⁵ are methyl.

In another embodiment, the invention provides a compound selected from the group consisting of: Wherein R ¹¹ is as defined above.

In another aspect, the GGA derivative used herein is a compound of formula (V): Wherein m is 0 or 1; n is 0, 1, or 2; each of R ¹ and R ² is independently C ₁ -C ₆ alkyl, or R ¹ and R ² are taken together with the carbon atom to which they are attached, optionally a C ₅ -C ₇ cycloalkyl ring substituted with 1-3 C ₁ -C ₆ alkyl groups; each R ³ , R ⁴ and R ⁵ is independently hydrogen or C ₁ -C ₆ alkyl; The following groups:

When X is bonded via a single bond, X is -O-, -NR ⁷ -, or -CR ⁸ R ⁹ -, and when X is bonded via a double bond, X is -CR ⁸ -; Y ¹ is Hydrogen or -OR ¹⁰ ; Y ² is -OR ¹¹ , -NHR ¹² or -O-CO-NR ¹³ R ¹⁴ , or Y ¹ and Y ² are joined to form an oxy group (=O), an imido group (= NR ¹⁵ ), fluorenyl (=N-OR ¹⁶ ), or substituted or unsubstituted vinyl (=CR ¹⁸ R ¹⁹ ); R ⁶ is C ₁ -C ₆ alkyl, 1-3 alkoxy a C ₁ -C ₆ alkyl group substituted with a 1-5 halogen group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, a C ₃ -C ₁₀ cycloalkyl group, a C ₃ -C ₈ heterocyclic ring a C ₆ -C ₁₀ aryl group, a C ₂ -C ₁₀ heteroaryl group, or NR ²⁰ R ²¹ , wherein each cycloalkyl or heterocyclic group may be optionally substituted with 1-3 C ₁ -C ₆ alkyl groups And wherein each aryl or heteroaryl group may be independently substituted by 1-3 nitro groups and a C ₁ -C ₆ alkyl group; R ⁷ is hydrogen or may form a random phase together with R ⁶ and the inserted atom; - 3 C ₁ -C ₆ alkyl group substituted 5-7 membered rings; each R ⁸ and R ⁹ is independently hydrogen, C ₁ -C ₆ alkyl, -COR ⁸¹ , -CO ₂ R ⁸¹ , or - CONHR ^82, or R ⁸ is formed can be arbitrarily substituted with 1-3 C ₁ -C ₆ alkyl group of 5-7 members with R ⁶ and the insertion of atoms Alkyl or heterocyclyl ring; R ¹⁰ is C ₁ -C ₆ alkyl group; R ¹¹ and R ¹² each independently lines C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, -CO ₂ R ¹⁷ , or -CON(R ¹⁷ ) ₂ ; R ¹³ is

R ¹⁴ is hydrogen or C ₁ -C ₆ alkyl; R ¹⁵ is C ₁ -C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl, which may be optionally substituted with 1-3 C ₁ -C ₆ alkyl groups Or for R ¹⁶ is hydrogen, C ₁ -C ₆ alkyl, which may be optionally substituted with a substituent of the following group: -CO ₂ H or an ester thereof, or a C ₆ -C ₁₀ aryl group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, a C ₃ -C ₁₀ cycloalkyl group, or a C ₃ -C ₈ heterocyclic group, wherein each cycloalkyl group, heterocyclic group or aryl group is optionally substituted with 1-3 alkyl groups Each R ¹⁷ is independently hydrogen, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkyl, which may be optionally substituted with from 1 to 3 substituents selected from the group consisting of: -CO ₂ H or An ester, an aryl group, a C ₃ -C ₈ heterocyclic group, or two R ¹⁷ groups together with a nitrogen atom to which they are bonded form a 5-7 membered heterocyclic ring; R ¹⁸ is hydrogen or a C ₁ -C ₆ alkyl group; R ¹⁹ is hydrogen, C ₁ -C ₆ alkyl, which may be substituted by 1-3 hydroxyl groups, -CHO, or -CO ₂ H or an ester thereof; one or both of R ²⁰ and R ²¹ are independently Hydrogen, C ₁ -C ₆ alkyl, which may be optionally substituted with substituents of the following group: -CO ₂ H or its ester, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₈ heterocyclic, C ₂ -C ₁₀ aryl, or C ₂ -C ₁₀ heteroaryl, or C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₈ heterocyclic, C ₆ -C ₁₀ aryl, or C ₂ -C ₁₀ a heteroaryl group in which each cycloalkyl group, heterocyclic group, aryl group or heteroaryl group Arbitrarily substituted with 1-3 alkyl groups, or R ²⁰ and R ²¹ together form a 5-7 membered heterocyclic ring with the nitrogen atom to which they are bonded, and if only one of R ²⁰ and R ²¹ is as hereinbefore defined in the, Then the other is R ⁸¹ is C ₁ -C ₆ alkyl; and R ⁸² is: The prerequisite is that when X is bonded via a single bond, and R ⁸ or R ^{9 is} not -CONHR ¹² , Y ¹ and Y ² are joined to form an imine group (=NR ¹⁵ ), and R ¹⁵ is: Or Y ² is -O-CO-NR ¹³ R ¹⁴ ; or a prerequisite is when Q is: And when R ^{8 is} not -CONHR ⁸² , Y ² is -O-CO-NR ¹³ R ¹⁴ ; or a prerequisite thereof is that when Q is -O-CO-NR ²⁰ R ²¹ , then R ²⁰ and R ^{21 are} at least one The person is:

In one embodiment, the GGA derivative used is a compound of the formula:

In some aspects, the compound used is a compound of formula (XXI) or (XXII): Or a pharmaceutically acceptable salt thereof, wherein R ¹¹⁴ and R ¹¹⁵ are independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₆ alkenyl, C _{a 1} -C ₆ alkynyl group, optionally substituted C ₆ -C ₂₀ aryl group, optionally substituted C ₆ -C ₂₀ aryl-C ₁ -C ₆ alkyl group, optionally substituted heteroaryl group and Optionally substituted heteroaryl-C ₁ -C ₆ alkyl, each heteroaryl having 2 to 14 ring carbon atoms and 1 to 6 ring heteroatoms (preferably, selected from N, O, S and P), wherein each substituted aryl or substituted heteroaryl is independently substituted with from 1 to 3 substituents selected from the group consisting of -OH, halogen, C ₁ -C ₆ alkyl, C _{a 1} -C ₆ alkoxy group, a -NO ₂ group and a R ¹¹⁰ R ¹¹¹ group; or R ¹¹⁴ and R ¹¹⁵ together with the carbon atom to which they are attached may be optionally substituted by 1-3 C ₁ -C ₆ alkyl groups. a C ₃ -C ₇ cycloalkyl ring; R ¹¹⁶ and R ¹¹⁷ are independently hydrogen or C ₁ -C ₆ alkyl; each R ¹¹⁰ and R ¹¹¹ are independently hydrogen, C ₁ -C ₆ alkyl or C ₆ - a C ₂₀ aryl group; or R ¹¹⁰ and R ¹¹¹ together with the nitrogen atom to which they are attached form a C ₃ -C ₇ heterocyclic ring; wherein each aryl group of R ¹¹⁰ and R ¹¹¹ is optionally passed through 1-3 C ₁ -C ₆ alkane base C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkanoyl group, a C ₁ -C ₆ alkanoyl group, C ₁ -C ₆ alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethanesulfonic Substituted, trifluoromethoxy, NR ¹¹² R ¹¹³ , or S(O) ₂ NR ¹¹² R ¹¹³ group wherein each R ¹¹² and R ¹¹³ are independently hydrogen or C ₁ -C ₆ alkyl; each R ¹¹⁸ And R ¹¹⁹ are independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl and the group of formula (XXIII): Wherein R ¹¹⁴ -R ¹¹⁷ and n are as defined herein; Y ₅ is -P(=O)(OR ¹¹⁸ )(OR ¹¹⁹ ), -CO ₂ R ⁵²⁰ or -SO ₂ OR ⁵²⁰ , wherein R ⁵²⁰ is selected from The following groups: hydrogen and C ₁ -C ₆ alkyl; Z is Wherein R ¹²¹ is hydrogen or C ₁ -C ₆ alkyl; A is a C ₁ -C ₅ alkylene group which may have a substituent selected from the group consisting of -OH, halogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy; r is 1, 2, 3, 4 or 5; and n is 0, 1, 2, 3, 4 or 5.

In one aspect, the GGA derivative used herein is a compound of the formula:

Wherein R ₃₀₁ is a lower (e.g., C ₁ -C ₆ ) alkyl group which may be optionally substituted with from 1 to 4 substituents selected from the group consisting of halogen, hydroxy; lower alkyl; lower alkoxy Halogenated lower alkyl; halogenated lower alkoxy; cyano; 5- or 6-membered (hetero) aromatic ring which may be via hydroxy, lower alkyl, lower alkoxy, halogen, amine Substituted, lower alkylamino substituted; cyano, nitro; and other (substituted) (hetero) aromatic rings; R ₃₀₂ is hydrogen or C ₁ -C ₄ alkyl; comprises both R and S configurations. R ₃₀₃ , R ₃₀₄ and R ₃₀₅ are independently selected from hydrogen, substituted and unsubstituted C ₁ -C ₄ alkyl; R ₃₀₆ is CH(O) or C _m H _2m -X ₆ , wherein m is 1- 3 and X ₆ is -H, -OH or a 5- or 6-membered (hetero) aromatic ring; and Y ₅ is -C(O)- or -C(=NOR ₇ )-, wherein R ₃₀₇ is hydrogen or C _1- C ₄ alkyl.

In another aspect, the GGA derivative used is a compound of the formula: Wherein R ⁴⁰¹ and R ⁴⁰² each represent a hydrogen atom, a lower alkyl group, a cycloalkyl group, an alkenyl group or an alkynyl group, an aryl group which may be substituted, an aralkyl group in which the aryl group may be substituted, or a heteroaryl group Or heteroaralkyl: R ⁴⁰³ and R ⁴⁰⁴ each represent a hydrogen atom, a lower alkyl group or an alkali metal; Y ₅ represents a group represented by the formula: Wherein R ⁴⁰⁵ and R ⁴⁰⁶ each represent a hydrogen atom, a lower alkyl group, or an alkali metal, or a group represented by the formula: -CO ₂ R ⁴⁰⁷ (wherein R ⁴⁰⁷ represents a hydrogen atom, a lower alkyl group or an alkali metal) ; Z ₅ represents a group represented by the formula: -(CH ₂ ) _m - (wherein m is an integer of 0 to 3), a group represented by the formula: -(CH ₂ ) _p -CH=CH-( CH ₂ ) _q - (where p is 0 or 1 and q is 1 or 2), or a group represented by the formula:

Wherein R ⁴⁰⁸ represents a hydrogen atom or a lower alkyl group; A represents an alkyl chain having 1 to 5 carbon atoms and may have a substituent on each carbon atom; and r is an integer of 0 or 1 to 5; Zero or an integer from 1 to 5.

In some embodiments, the compounds isolated herein include:

( 6E,10E,14E )-7,11,15,19-tetramethyl twenty-6,10,14,18-tetraen-3-one

( 6E,10E )-7,11,15-trimethylhexades-6,10,14-trien-3-one

( E )-7,11-Dimethyl-12-6,10-dien-3-one

( 5E,9E,13E )-1,1,1-trifluoro-6,10,14,18-tetramethyl-19-,9,13,17-tetraen-2-one

( 5E,9E )-1,1,1-trifluoro-6,10,14-trimethylpentade-5-5,9,13-trien-2-one

( E )-1,1,1-Trifluoro-6,10-dimethylundec-5,9-dien-2-one

And corresponding ethyl and other C ₁ -C ₆ alkyl esters, and corresponding cis isomers.

In the present disclosure, if a variable (such as R ¹ ) is used to represent more than one functional group, those skilled in the art will readily appreciate the definition of the variable based on the chemical formula to which the variable refers.

Synthesis method of GGA and GGA derivatives

In various aspects, provided herein are methods for preparing compounds of formula (XXXI) and derivatives thereof, and intermediates useful in the synthesis thereof.

Or a salt thereof, wherein the definition of the variable in the structures (XXXI) to (YVIII) is as defined in the above formula (II).

In one embodiment, X ³⁰ and Y ³⁰ together with the carbon atom to which they are attached form a ring of the formula: Wherein each of X ³¹ and X ³² is independently O or S; q is 1 or 2; each X ³³ is independently C ₁ -C ₆ alkyl; and t is 0, 1, 2 or 3.

In one aspect, the GGA derivative has the formula YIX:

Or a tautomer or pharmaceutically acceptable salt thereof, wherein X, Y, R ³¹ and R ³² are as defined herein; and n is 1, 2, 3, 4 or 5.

In another aspect, the GGA derivative has the formula YX:

Or a tautomer or pharmaceutically acceptable salt thereof, wherein R ³¹ , R ³² and n are as defined herein.

In another aspect, the GGA derivative has the formula (YXI)-(YXV): Or a tautomer or pharmaceutically acceptable salt thereof, wherein X ³⁰ and Y ³⁰ are each independently OR ³⁶ , SR ³⁶ , or X ³⁰ and Y ³⁰ together with the carbon atom to which they are attached form 2 oxygen and/or a sulfur atom, and optionally a 5-7 membered heterocyclic ring substituted with 1-3 C ₁ -C ₆ alkyl groups, each R ³⁶ is independently a C ₁ -C ₆ alkyl group, and each R ³⁷ group is independently H or C ₁ -C ₆ alkyl, and n is an integer from 1 to 5.

In one embodiment, X ³⁰ and Y ³⁰ together with the carbon atom to which they are attached form a cyclic ketal having 2 oxygen, 2 sulfur, or 1 oxygen and 1 sulfur atom.

In one embodiment, X ³⁰ and Y ³⁰ together with the carbon atom to which they are attached form a dioxolane, an oxathiolane, a dithiolane, two A dioxane, oxathiane or dithiane ring.

The present invention provides methods for synthesizing GGA derivatives, cis-trans isomers, and subformulas thereof.

In one aspect, a method for preparing a GGA derivative of formula (XXXI) is provided. The method comprises contacting a compound of formula (XXXII) with an acid catalyst under conditions suitable for the hydrolysis of a compound of formula (XXXII) to yield a compound of formula (XXXI).

In one embodiment, conditions suitable for hydrolyzing a compound of formula (XXXII) to produce a compound of formula (XXXI) include contacting a compound of formula (XXXII) with an acid catalyst in an inert solvent at a suitable temperature. In one embodiment, the acid catalyst used in the process is selected from the group consisting of aqueous acetic acid, formic acid, trifluoroacetic acid, sulfuric acid, hydrochloric acid, methanesulfonic acid, alkyl or aralkyl sulfonic acid or Lewis acid. . Preferably, the acid is used in a catalytic amount.

In another aspect, a method for preparing a GGA derivative of formula (XXXII) is provided. The process comprises olefinating (XXXIII) under conditions suitable for the olefination of formula (XXXIII) to yield a compound of formula (XXXII).

In one embodiment, the olefination reaction is carried out using a Wittig reaction. A deuteration reaction or a deuteration reaction means that a carbonyl compound such as an aldehyde or a ketone is reacted with hydrazine to produce an olefin. A typical deterrent reaction involves deprotonation of a phosphonium salt by a base to form a phosphorane and reacting it with an aldehyde. The phosphonium salt or deuteration reagent used in the reaction can be obtained by reacting a phosphine (for example, triphenylphosphine) with a primary or secondary halide under heating in the presence or absence of a solvent.

In one embodiment, conditions suitable for the olefination of a compound of formula (XXXIII) to produce a compound of formula (XXXII) include, for example, the aldehyde of formula (III) in the presence of a base in a suitable solvent. A positive phosphine reaction. In one embodiment, the olefination reaction of a compound of formula (XXXIII) comprises contacting compound (XXXIII) with a deuterium reagent such as C(R ³¹ R ³² )=P(R ^z ) ₃ (wherein R ^z is, for example Triphenylphosphine). In some embodiments, a composition comprising a compound of formula (XXXIII) and a deuterium reagent (eg, C(R ³¹ R ³² )=P(R ^z ) ₃ ) is provided. Suitable solvents include, for example, aliphatic or aromatic hydrocarbons such as, for example, hexane, benzene or toluene, and ethers such as, for example, diethyl ether and tetrahydrofuran, or guanamine such as, for example, dimethylformamide or hexamethyl. Triammonium phosphate. In some cases, an alcohol or dimethyl hydrazine may be used as a solvent. Suitable bases for the deuteration reaction include metal alkoxides such as, for example, sodium ethoxide, metal hydrides such as, for example, sodium hydride, metal guanamines such as, for example, sodium amide, and organometallic compounds such as For example, phenyl lithium or butyl lithium). The vinyl group formed in the compound of formula (XXXII) may have specificity and positional selectivity.

In one embodiment, the olefination reaction is carried out using a Wittig-Horne reaction. In other embodiments, the olefination reaction is carried out using a Peterson olefination reaction. Those skilled in the art will be aware of the conditions that are suitable for use in these reactions. For example, the Wittig-Horne reaction can be carried out at low temperatures using a deuterium reagent (as described for the detergency reaction, but using a lithium base such as, for example, n-butyllithium). In the Peterson olefination reaction, for example, an α-fluorene alkylated carbanion is added to a carbonyl compound of the formula (XXXIII) to produce two diastereomeric β-hydroxydecanes which can be isolated and Further converted to olefins, respectively.

In still another aspect, a method for preparing a GGA derivative of formula (XXXIII) is provided. The method comprises oxidizing a compound of formula (XXXIV) under suitable conditions to produce a compound of formula (XXXIII).

In another aspect, a method for preparing a GGA derivative of formula (XXXVII) is provided. The process comprises oxidizing a compound of formula (XXXVIII) under suitable conditions to yield a compound of formula (XXXVII).

In another aspect, a method for preparing a GGA derivative of formula (YI) is provided. The method comprises oxidizing a compound of formula (YII) under suitable conditions to produce a compound of formula (YI).

In another aspect, a method for preparing a GGA derivative of formula (XV) is provided. The method comprises oxidizing a compound of formula (YVI) under suitable conditions to produce a compound of formula (YV).

In some embodiments, suitable conditions for oxidizing a compound of formula (XXXIV), (XXXVIII), (YII), (YVI) include subjecting the compound to a Moffatt oxidation reaction. As will be appreciated by those skilled in the art, the Moffatt oxidation reaction is activated by dimethyl sulfoxide (DMSO) in the presence of an acid with a carbodiimide such as dicyclohexylcarbodiimide (DCC). Oxidizing a primary alcohol and a secondary alcohol to produce an alkoxy fluorene De, it is rearranged to produce aldehydes and ketones, respectively (K. E. Pfitzner and J. G. Moffatt, J. Am. Chem. Soc., 85, 3027 (1963)). Swern oxidation reactions can also be used, as is well known to those skilled in the art, and in some embodiments, the reaction is carried out using DMSO and oxalic acid chloride at low temperatures.

Other methods suitable for the oxidation of alcohols to aldehydes can be used in some embodiments. For example, the alcohol can be oxidized by argon trioxide pyridine complex in the presence of an alkylamine base (e.g., triethylamine) in the presence of an alkylamine base (e.g., triethylamine) under Parikh-Doering oxidation conditions. In other embodiments, the alcohol compound can be oxidized under Swern oxidation conditions using oxalic acid chloride, dimethyl hydrazine (DMSO), and an organic base such as an alkylamine base such as triethylamine.

In another aspect, a method for preparing a GGA derivative of formula (XXXIV) is provided. The method comprises reducing a compound of formula (XXXV) under suitable conditions to yield a compound of formula (XXXIV).

In another aspect, a method for preparing a GGA derivative of formula (XXXVIII) is provided. This method comprises oxidizing a compound of formula (XXXIX) under suitable conditions to yield a compound of formula (XXXVIII).

In another aspect, a method for preparing a GGA derivative of formula (XII) is provided. The process comprises oxidizing a compound of formula (XIII) under suitable conditions to yield a compound of formula (XII).

In another aspect, a method for preparing a GGA derivative of formula (YVI) is provided. The process comprises oxidizing a compound of formula (YVII) under suitable conditions to yield a compound of formula (YVI).

Reducing agents suitable for reducing the acid of formula (XXXV), (XXXIX) or (YIII) or (YVII) include reducing hydrides, preferably aluminum hydride or boron hydride, as will be appreciated by those skilled in the art. The compound is more preferably a metal aluminum hydride (wherein the metal is a Group I or Group II metal such as lithium, sodium, potassium, calcium, magnesium, etc.). Particularly preferred metal aluminum hydrides include lithium aluminum hydride (LAH), sodium aluminum hydride, and mixtures thereof. The reduction reaction is usually carried out in an aprotic solvent such as an ether (for example, tetrahydrofuran) or an aromatic hydrocarbon (for example, benzene and toluene) at a temperature as low as reflux, and a compound of the formula (XXXV) per mole is used. 0.5 to about 3.0 moles of hydride reducing agent is carried out. In one embodiment, the preferred reducing agent is lithium aluminum hydride. Suitable solvents include two Alkane, toluene, diethyl ether, tetrahydrofuran (THF), dipropyl ether, and the like. In one embodiment, the preferred solvent is diethyl ether or THF.

In another aspect, a method for preparing a GGA derivative of formula (XXXV) is provided. The method comprises reacting a compound of formula (XXXVI) under suitable conditions to yield a compound of formula (XXXV).

In another aspect, a method for preparing a GGA derivative of formula (XXXIX) is provided. This method comprises reacting a compound of formula (Y) under suitable conditions to yield a compound of formula (IX).

In another aspect, a method for preparing a GGA derivative of formula (YIII) is provided. The method comprises reacting a compound of formula (YIV) under suitable conditions to produce a compound of formula (YIII).

In some embodiments, suitable conditions include subjecting the allyl alcohol of formula (XXXVI), (Y), or (YIV) to a Johnson-Claisen rearrangement to produce a gamma, delta-unsaturated ester, such as formula (XXXV). In one embodiment, the compound of formula (XXXVI) is condensed with tri-(C ₁ -C ₆ )alkyl orthoacetate in the presence of an acid in a reaction inert solvent, and the intermediate allylene is The alcohol ether was further rearranged without isolation. The orthoacetate used in the process is preferably selected from the group consisting of trimethyl orthoacetate and triethyl orthoacetate. In one embodiment, the orthoacetate has the formula CH ₃ C(OR ³⁰ ) ₃ wherein R ³⁰ is a C ₁ -C ₆ alkyl group. In some embodiments, the acid is a weak acid, preferably a simple carboxylic acid such as propionic acid or isobutyric acid, or an alkane or an arene sulfonic acid such as p-toluenesulfonic acid. The process is carried out at elevated temperature (preferably reflux temperature) under conditions in which the alcohol produced by the process can be removed from the reaction mixture.

In another aspect, a method for preparing a GGA derivative of formula (XXXVI) is provided. This method comprises alkylating a compound of formula (XXXVII) with R ³³ C(-)=CH ₂ under suitable conditions to yield a compound of formula (XXXVI).

In another aspect, a method for preparing a GGA derivative of formula (Y) is provided. The process comprises alkenylating a compound of formula (YI) with R ³⁴ C(-)=CH ₂ under suitable conditions to yield a compound of formula (Y).

In another aspect, a method for preparing a GGA derivative of formula (YIV) is provided. The process comprises alkenylating a compound of formula (YV) with R ³⁵ C(-)=CH ₂ under suitable conditions to yield a compound of formula (YIV).

R ³³ , R ³⁴ and R ³⁵ are as defined above. In some embodiments, suitable conditions for the alkenylation of formula (XXXVII), (YI), and (YV) include contacting a compound of formula (XXXVII) with a suitable organometallic reagent in a reaction inert solvent. Preferably, the organometallic reagent for C-alkenylating the carbonyl compound to the allyl alcohol comprises a magnesium halide or lithium moiety. Suitable inert solvents for use in the process will be apparent to those skilled in the art. In one embodiment, the solvent is THF or diethyl ether.

In another aspect, a method for preparing a GGA derivative of formula (YVII) is provided. The method comprises the step of formulating a compound of formula (YVIII) The reaction is carried out under suitable conditions to give a compound of formula (YVII).

In some embodiments, suitable conditions for forming a ketal, a thioketal or an oxathioketal (having an -OCS- moiety) include reacting a carbonyl compound of formula (YVIII) with a suitable alcohol, The α,ω-diol, thiol, α,ω-dithiol or ω-hydroxy thiol solvent is reacted under acidic conditions. In one embodiment, the ester of formula (YVIII) is reacted with a suitable alcohol such as, for example, ethylene glycol, mercaptoethanol, and 1,2-dithioethanol in the presence of a suitable acid catalyst, followed by Boiling off the water. Suitable acid catalysts include, for example, strong mineral acids such as sulfuric acid, hydrochloric acid, hydrofluoroboric acid, hydrobromic acid, p-toluenesulfonic acid, succinic acid, methanesulfonic acid, and the like. Various resins containing protonated sulfonic acid groups are also useful because they can be easily recovered after the reaction is completed. Examples of acids also include Lewis acids. For example, various complexes of boron trifluoride and BF ₃ such as, for example, boron trifluoride diethyl ether. Ceria, acid alumina, titania, zirconia, various acidic clays, and mixed alumina or magnesium can be used. Activated carbon derivatives containing mineral acids, sulfonic acids or Lewis acid derivatives can also be used.

In one aspect, a method for preparing a GGA derivative of formula (YX) is provided. The process comprises contacting a compound of formula (YIX) with an acid catalyst under conditions suitable for the hydrolysis of a compound of formula (YIX) to yield a compound of formula (YX).

In one embodiment, the conditions suitable for the hydrolysis of a compound of formula (XXXII) to yield a compound of formula (XXXI) include reacting a compound of formula (XXXII) with an acid catalyst at a suitable temperature in a compatible solvent. In contact.

In one embodiment, the acid catalyst used in the process is selected from the group consisting of aqueous acetic acid, formic acid, trifluoroacetic acid, sulfuric acid, hydrochloric acid, methanesulfonic acid, alkyl or aralkyl sulfonic acids, or Lewis acids.

In one embodiment, the GGA prepared in accordance with the present invention is a 5-trans GGA or a substantially pure 5-trans GGA that is selectively free of cis GGA or substantially free of cis GGA. In other embodiments, the GGA prepared in accordance with the present invention is a 5-cis GGA or a substantially pure 5-cis GGA that is selectively free of trans GGA or substantially free of trans GGA.

The starting materials for the reactions described herein are well known compounds or can be prepared by known procedures or modifications apparent to them. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Company (Milwaukee, Wisconsin, USA), Bachem (Torrance, California), EmkaA-Chemce or Sigma (St. Louis, Missouri, USA). Others may be described by standard reference text Prepared by procedures or their explicit modifications, such as Fieser and Fieser's Reagents for Organic Synthesis, Vol. 115 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Vol. 15 and Supplementary Information (Elsevier Science Publishers, 1989), Organic Reactions, Vol. 140 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989) .

Acetyl propionates (such as methyl acetate, ethyl acetate) can be passed via ethylene, mercaptoethanol or ethyl-1,2-dithiol under acidic conditions that promote the removal of water. The reaction is converted to the corresponding ketal (X = Y = O), hemithioketal (X = O, Y = S) or dithioketal (X = Y = S). Typical acid catalysts include p-toluenesulfonic acid, or acetic acid and boron trifluoride-etherate. Solvents for such conversion include benzene, toluene and dichloromethane. Water can be removed via azeotropic distillation or via reaction with an orthoester such as triethyl orthoformate or triethyl orthoacetate. (Reaction 1)

Conversion of the ketal ester from reaction 1 to the corresponding aldehyde can be accomplished in a single step as shown in Reaction 2, which is a hindered active metal hydride (such as diisobutyl) in diethyl ether at a reduced temperature. The aluminum hydride was reduced and then quenched with ethyl acetate to consume excess reagent. The temperature used for such reactions must generally be kept below -35 ° C to minimize excessive reduction to alcohol. (Reaction 2)

Alternatively, higher yields can be prepared in two separate steps And a higher purity aldehyde. The first step, Reaction 3, involves the complete reduction of the ester to the corresponding alcohol with a stronger reducing agent such as lithium aluminum hydride in = diethyl ether or THF. This reduction reaction is followed by oxidation of the alcohol to the aldehyde via Reaction 4 (by one of several methods listed below). (Reaction 4)

The oxidation of alcohols to aldehydes using chromium trioxide in pyridine has been reported. Alternatively, the oxidation reaction can be carried out by any of dimethyl hydrazine and various dehydrating agents. Published examples include various mercapto chlorides, anhydrides, and carbodiimides.

These reactions typically require temperatures below -35 ° C to prevent side reactions. In the presence of triethylamine, the process using sulfur trioxide-pyridine complex can be carried out with minimal side reactions at room temperature. (Reaction 5)

The aldehyde is reacted with 2-propenyllithium or its Grignard equivalent to produce allyl alcohol. The alcohol can be converted to a highly stereoselective olefin ester in high yield. (Reaction 6)

The product is then subjected to a two-cycle reaction 3 to 6 conversion reaction to produce an ester. This ester is then reduced and oxidized according to reactions 3 and 4 to obtain the alcohol (in reaction 7) and the aldehyde (in reaction 8).

As shown in Reaction 9, the terminal olefin was added via a deuteration reaction using propyltriphenylphosphine ylide (produced from commercially available isopropyl (triphenyl)phosphonium bromide).

The final product is produced by hydrolysis of a ketal, a hemithioketal or a dithioketone.

Other methods for making GGA or certain GGA derivatives as used herein are described in PCT Publication No. WO 2012/031028 and PCT. In the application No. PCT/US2012/027147, the entire contents of each of which is incorporated herein by reference. Other GGA derivatives can be prepared by appropriate substitution of the reagents and starting materials, which will be apparent to those skilled in the art after reading this disclosure.

Preferably, the reaction is carried out for a sufficient period of time in a suitable inert solvent (which will be apparent to those skilled in the art after reading the disclosure) to ensure that the reaction is substantially complete, which may be accomplished by a thin layer of color. The layer analysis method, ¹ H-NMR, and the like were observed. As is well known to those skilled in the art, the reaction mixture can be heated if it is desired to accelerate the reaction. If desired, various methods known in the art, such as crystallization, precipitation, analytical column chromatography, etc., will be apparent to those skilled in the art after reading this disclosure. The compound was purified.

The compounds used in the present invention may, for example, be in a variety of well-known methods after substituting the reactants and/or changing the reaction conditions (this will be apparent to those skilled in the art after reading this disclosure). Compound Synthesis of (III-A):

Where n, R ¹ -R ⁵ and It is as defined in the above formula (I). Compounds of formula (III-A) are themselves prepared by methods well known to those skilled in the art, such as, but not limited to, those described in PCT Patent Application Publication No. WO 2012/031028 and PCT Patent Application Publication No. PCT/US2012/ No. 027147 (each see above). Illustrative and non-limiting methods for the synthesis of compounds of formula (III-A) wherein n is 1 are shown graphically below.

The starting compound (iii) is synthesized as a β-ketoester (iv) in the presence of a base such as an alkoxide (which is synthesized from the compound (i) via addition of an isoprene derivative as described herein) Alkylation to provide the corresponding beta-ketoester (v). Compound (v), upon alkaline hydrolysis, is then subjected to decarboxylation to provide the ketone (vi). The ketone compound (vi) is converted into a conjugated ester (viii) after the Wittig Horner reaction with the compound (vii). The compound (viii) is reduced with, for example, LiAlH ₄ to provide an alcohol (ix).

As is clear to those skilled in the art, the compound of formula (III) wherein n is 2 is via repeated alkylation with a β-ketoester, hydrolysis, decarboxylation, Wittig Horner olefination and LiAlH ₄ reduction. The reaction sequence is synthesized.

Certain illustrative and non-limiting compounds synthesis methods used in the present invention are shown in the following figures. As will by those skilled in the art is apparent, wherein Q ¹ is - (C = S) - or -SO ₂ - of the compound is via a carbonyl group substituted reactants used to synthesize the.

As indicated above, R ^E is an alkyl group.

The alcohol functional compound (ix) is an intermediate used in the preparation of the compounds used in the present invention. Compound (x) wherein L is an R ^s SO ₂ - group is prepared by reacting compound (ix) with R ^s SO ₂ Cl in the presence of a base. The conversion of the compound (iii) into the compound (x) illustrates a method of adding an isoprene derivative to a compound which is suitable for the preparation of the compound (iii) from the compound (i). The intermediate (ix) containing various R ¹ -R ⁵ substituents was prepared according to the chart of the following examples. The conversion of the compound (iii) into the compound (x) illustrates a method of adding an isoprene derivative to a compound which is suitable for the preparation of the compound (iii) from the compound (i).

The intermediate prepared above is converted to a compound useful in the present invention by the method illustrated in the following scheme:

As used herein, for example, but not limited to, m is 0 or 1, and R ¹ -R ⁵ are as defined herein, preferably alkyl, or more preferably methyl. The intermediate (ixa) prepared according to the above chart is converted to the amine intermediate (ixb) via the corresponding bromide. The intermediates (ixa) and (ixb) are converted to the compounds useful in the present invention by reaction with a suitable isocyanate or aminoguanidinium chloride, which is prepared by methods known in the art. The thiocarbamate and thiourea of the present invention are according to the above method, and are isothiocyanate (R ¹⁸ -N=C=S) or thioaminomethylhydrazine chloride (R ¹⁸ -NH- C(=S)Cl or R ¹⁸ R ¹⁹ NC(=S)Cl) is prepared by substituting isocyanate or aminomethane chloride. These and other compounds for use in the present invention may also be prepared by methods known in the art, which may require modification. These modifications will be apparent to those skilled in the art after reading this disclosure. Intermediates containing different R ¹ -R ⁵ substituents for use in the synthesis of the present invention are illustrated in the Examples section and/or are well known to those skilled in the art.

Certain GGA derivatives used herein are synthesized as shown in the graph below.

Certain compounds used herein are obtained by reacting compound (x) with an anion Q(-) which can be produced by reacting compound QH with a base. Non-limiting examples of suitable bases include hydroxides, hydrogenation , guanamine, alkoxide, etc. The various compounds used in the present invention in which the carbonyl group is converted to an imine, an anthracene, an alkoxyimine, an enol urethane, a ketal, and the like are prepared according to a well-known method.

Other methods for making the compounds used in the present invention are illustrated graphically below:

The metallization reaction is carried out by passing a ketone with a base such as a dimethyl sulfonium anion, a hindered guanamine base such as diisopropyl decylamine or hexamethyldioxane azide, and a corresponding metal cation M The reaction proceeds. The aminocarbonyl chloride or isocyanate is prepared, for example, by reacting an amine (R ¹⁴ ) ₂ NH with phosgene or an equivalent reagent well known to those skilled in the art.

The β-ketoester is hydrolyzed while ensuring that the reaction conditions do not result in decarboxylation. Various acidic activators (such as carbonyldiimidazole or O-benzotriazole-N,N,N',N'-tetramethylurea-hexafluorophosphate (HBTU)) which are well known to those skilled in the art will The acid is activated and reacts with the amine.

Various other compounds used in the present invention are prepared according to known methods from the compounds produced in the above scheme.

As indicated above, R ^E is an alkyl group.

The intermediates prepared as described above are converted to the compounds used in the invention according to the following diagram:

Compound (viii) is hydrolyzed to the carboxylic acid (x) which is then converted to the mercapto chloride (xi). Compound (xi) is reacted with a suitable nucleophile such as hydrazine, hydroxylamine, amino alcohol, or amino acid and the intermediate dehydrated to provide a compound of formula (I). Alternatively, allyl alcohol (ix) is oxidized to the aldehyde (xi) which is then reacted with cyanohydrin or cyano-p-toluenesulfonyl methane to provide additional compounds useful in the present invention.

GGA derivatives useful in the present invention may also be employed by methods known in the art and those disclosed herein by olefin-aryl, olefin-heteroaryl or olefin-akene coupling (such as Heck, Stille or Suzuki coupling). To synthesize. Such methods can be carried out using (vi) intermediates (xii) which can be Heck, Stille or Suzuki coupled to provide the compounds useful in the present invention, under conditions well known to those skilled in the art.

Similarly, the higher and lower isoprenyl homologues of intermediates (x), (xi) and (xii) which are prepared according to the methods disclosed herein can be used in the preparation of the invention. Other compounds.

The compounds used in the present invention can also be prepared as shown below

L and Q are as defined herein, preferably, Ar is an aryl group (such as phenyl), the base used is an alkoxide (such as a third butoxide), a hydride or an alkyl lithium (such as a positive Butyl lithium). The methods of carrying out the above-described steps are well known to those skilled in the art, as are the conditions, reagents, solvents and/or additives used to carry out the reaction and obtain the compound of formula (I) in the desired stereochemical configuration. Also well known.

Other methods for making the compounds used in the present invention are illustrated graphically below: The metallization reaction is carried out by reacting a ketone with a base such as a dimethyl sulfonium anion, a hindered guanamine base such as diisopropyl decylamine or hexamethyldioxane azide, and a corresponding metal cation M. Come on. The aminocarbonyl chloride or isocyanate is prepared, for example, by reacting the amine R ¹³ R ¹⁴ NH with phosgene or an equivalent reagent well known to those skilled in the art.

The β-ketoester is hydrolyzed while ensuring that the reaction conditions do not result in decarboxylation. Various acid activators (such as carbonyldiimidazole or O-benzotriazole-N,N,N',N'-tetramethylurea-hexafluorophosphate (HBTU)) which are well known to those skilled in the art will The acid is activated and reacts with the amine. Some other methods of preparing conjugates are shown below.

As indicated above, R is a memantine or riluzole residue.

Preparation method of co-crystal of the invention and isolation of GGA or GGA derivative with enhanced trans isomer content Example 1

GGA or a derivative thereof (about 10 g) containing a mixture of cis and trans isomers (the starting mixture) was added to a 250 ml three-necked round bottom flask containing isopropanol (about 75 ml). Thiourea (about 3 grams) is added to the mixture and can be selectively heated at about 90-95 ° C for about 15 hours. In reduction The solvent is distilled off at a low pressure at about 55-60 ° C to provide the co-crystal of the present invention.

If the GGA derivative is a solid, methanol (about 50 ml) is added to the co-crystal, stirred at 55-60 ° C for about 20 minutes and gradually cooled to about 20-25 ° C. The formed solid was filtered off, washed with methanol and dried under reduced pressure for about 3 hours to obtain a GGA derivative having a higher percentage of trans isomer than the percentage of the trans isomer contained in the starting mixture. .

If the GGA derivative is a liquid, the co-crystal is decomposed with water in the GGA, and the GGA or GGA derivative is extracted with petroleum ether or another suitable solvent (as is apparent to those skilled in the art). .

Example 2

GGA or GGA derivative (several milligrams) was dissolved in a little toluene (0.5-1.0 ml) and a saturated solution of thiourea in methanol (2-3 ml) was added. After several hours, the formed co-crystals were collected by centrifugation.

The co-crystals are washed with a little petroleum ether and then decomposed with water and the GGA or GGA derivative is extracted with petroleum ether or another suitable solvent, as is well known to those skilled in the art.

Claims (15)

a co-crystal or coprecipitate comprising geranylgeranylacetone (GGA), geranylgeranyl alcohol, or other GGA derivative, and urea and/or thiourea, wherein the GGA, geranyl group At least 80%, or at least 90%, or at least 95%, or at least 99% of the geranyl alcohol, or other GGA derivative, is present in the trans isomer form. A co-crystal or coprecipitate according to claim 1 of the patent, which is mixed with a composition comprising GGA, geranylgeranyl alcohol, or other GGA derivative, wherein GGA, geranium in the composition A geranyl alcohol, or other GGA derivative, exists in trans form as compared to GGA, geranylgeranyl alcohol, or other GGA derivatives that have been mistakenly cooperating for a portion of the cocrystal or coprecipitate Less substantial. A co-crystal or coprecipitate as claimed in claim 1 which is crystalline. A crystalline GGA derivative which exists in trans form or substantially in trans form. A process for preparing a co-crystal or coprecipitate of GGA, geranylgeranyl alcohol, or other GGA derivative with urea and/or thiourea, wherein the GGA, geranylgeranyl alcohol, or other GGA derivative At least 80%, or at least 90%, or at least 95%, or at least 99% is present in the form of the trans isomer, the method comprising GGA, geranylgeranol, or other GGA derivatives The mixture of cis and trans isomers is contacted with a composition comprising urea and/or thiourea under conditions sufficient to form the cocrystal or coprecipitate to provide the cocrystal or coprecipitate. The method of claim 5, further comprising isolating the GGA, geranylgeranyl alcohol, or other GGA derivative from the co-crystal to provide at least 80%, or at least 90%, or At least 95%, or at least 99%, of the trans isomer of GGA, geranylgeranyl alcohol, or other GGA derivatives. A method of separating GGA, geranylgeranyl alcohol, or other GGA derivatives present in trans or substantially in trans form, the method comprising containing GGA, geranylgeranol, or other a GGA derivative and a co-crystal or coprecipitate of urea and/or thiourea in which the GGA, geranylgeranyl alcohol, or other GGA derivative is mismatched in the co-crystal or coprecipitate The trans form or substantially in trans form) and the solvent which selectively dissolves the GGA, the geranylgeranol, or other GGA derivative or dissolves the urea and/or thiourea is sufficient for the dissolution Contact under the conditions. A method of preparing a compound of formula (XXXI): The method comprises: hydrolyzing a compound of formula (XXXII): Wherein: X ³⁰ and Y ³⁰ are each independently OR ³⁶ , SR ³⁶ , or X ³⁰ and Y ³⁰ together with the carbon atom to which they are attached form a ring of the formula: Wherein each R ³⁶ is independently C ₁ -C ₆ alkyl, each X ³¹ and X ³² are independently O or S; q is 1 or 2; each X ³³ is independently C ₁ -C ₆ alkyl; t is 0, 1, 2 or 3, and each R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ are independently H or C ₁ -C ₆ alkyl, or R ³¹ and R ³² together with the carbon atom to which they are attached A C ₅ -C ₆ cycloalkyl group optionally substituted with 1-3 C ₁ -C ₆ alkyl groups is formed. The method of claim 8, wherein the compound of formula (XXXII) is prepared: It comprises: a compound of formula (XXXIII): Contacting an agent of the formula (XXXIII) under conditions suitable for olefination of a compound of formula (XXXIII) to produce a compound of formula (XXXII): Wherein L ³⁰ is P(R ^Z ) ₃ , P(O)(R ^Z ) ₂ , SO ₂ R ^Z , or Si(R ^Z ) ₃ ; wherein R ^Z is C ₁ -C ₆ alkyl or aryl. A method of preparing a compound of formula (YXI): The method comprises: formulating a compound of formula (YXII): Wherein: X and Y are each independently OR ³⁶ , SR ³⁶ , or X ³⁰ and Y ³⁰ together with the carbon atom to which they are attached form a ring of the formula: Wherein each R ³⁶ is independently C ₁ -C ₆ alkyl, each X ³¹ and X ³² are independently O or S; q is 1 or 2; each X ³³ is independently C ₁ -C ₆ alkyl; t is 0, 1, 2 or 3, each R ³⁷ is independently H or C ₁ -C ₆ alkyl; and n is 1-5, oxidized under appropriate conditions to provide a compound of formula (YXI). The method of claim 10, wherein the compound of the formula (YXII) is prepared: It comprises: a compound of the formula (YXIII): Reduction under conditions suitable to provide a compound of formula (YXII). The method of claim 11, wherein the compound of the formula (YXIII) is prepared: It comprises: contacting a proacetate of the formula CH ₃ C(OR ³⁰ ) ₃ (wherein R ³⁰ is a C ₁ -C ₆ alkyl group) with a compound of the formula (YXIV): Wherein X, Y and R ^{7 are} as defined in the formula (XXXII). The method of claim 12, wherein the compound of the formula (YXIV) is prepared: It comprises: a compound of the formula (YXV): Contact with an anion of the formula R ³⁷ C(-)=CH ₂ . The method of claim 8 or 9, wherein R ^{31 -} R ³⁵ are methyl. The method of any one of claims 10-13, wherein R ³⁷ is a methyl group.