阅读说明：本技术 多环胺作为阿片受体调节剂 (Polycyclic amines as opioid receptor modulators ) 是由 王晓冬 钟华 于 2018-03-12 设计创作，主要内容包括：本发明提供了一类可用作阿片受体调节剂的多环胺类物质。本发明化合物可用于治疗和诊断方法中,包括治疗疼痛,神经系统失调,心脏失调,肠道失调,药物和酒精成瘾,药物过量,泌尿系统失调,呼吸系统失调,性功能障碍,牛皮癣,移植排斥或癌症。(The present invention provides a class of polycyclic amines useful as opioid receptor modulators. The compounds of the invention are useful in therapeutic and diagnostic methods, including the treatment of pain, neurological disorders, cardiac disorders, intestinal disorders, drug and alcohol addiction, drug overdose, urological disorders, respiratory disorders, sexual dysfunction, psoriasis, transplant rejection, or cancer.)

1. A compound having the structure of formula (I):

wherein:

a is substituted or unsubstituted: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl;

y is substituted or unsubstituted: alkyl, heteroalkyl, cycloalkyl and heterocycloalkyl;

q is substituted or unsubstituted: aryl, heteroaryl and none;

w is substituted or unsubstituted, saturated or unsaturated: (i) a 4-to 8-membered heterocycle comprising an N-substituent; or (ii) a 4-to 10-membered bicyclic or heterobicyclic ring, wherein at least one of the rings includes an N-substituent;

g is a substituted or unsubstituted alkyl group or a N atom;

z comprises substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and none;

if Z is null, T is null, but if Z is not null, T is selected from: (i) the following structural moieties: H. OH, NH₂、NO₂、-SO₂NH₂Halogen, and (ii) substituted or unsubstituted: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

when G is an alkyl group, N is an integer of 1 to 4, and when G is an N atom, N is 1;

R¹and R³Independently selected from H and substituted or unsubstituted: alkyl, heteroalkyl, 3-to 7-membered cycloalkyl, 3-to 7-membered heterocycloalkyl, aryl, and heteroaryl;

m is an integer from 0 to 8, and for R²、R⁴、R⁵And R⁶M may be the same or different, wherein R²、R⁴、R⁵And R⁶Each independently selected from H and substituted or unsubstituted: alkyl, heteroalkyl, 3-to 7-membered cycloalkyl, 3-to 7-membered heterocycloalkyl, and for any R²、R⁴、R⁵And R⁶When m is greater than 1, each of said plurality R²、R⁴、R⁵And R⁶The members of the chain may be the same or different; and further provided that when m is greater than 0, R²、R⁴、R⁵And R⁶Always less than or equal to the number of W ring positions available for covalent bonding; and

R¹and R³Or R is¹Or R³And Z, or R²And A, or R²And Y together with the groups to which they may be attached, optionally form a substituted or unsubstituted 3-to 7-membered ring.

2. The compound of claim 1, wherein for R²M is 1, for R⁴、R⁵And R⁶And m is 0.

3. The compound of claim 1, wherein for R²And for R⁴M is 1, for R⁵And R⁶And m is 0.

4. The compound of claim 1, wherein G is a methyl group and Z is a pyridine ring, whereby T is H.

5. The compound of claim 1, wherein the substituent group on a comprises one or more fluoro.

6. A pharmaceutically acceptable salt of the compound of claim 1.

7. The pharmaceutically acceptable salt of claim 6 which is the hydrochloride salt.

8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

9. The compound of claim 1, which is one of the following:

10. a method of preventing or treating a disease or condition selected from the group consisting of: reperfusion injury, cardiac disorder, pain, functional pain, inflammatory pain, peripherally mediated and neuropathic pain, non-somatic pain, arthritis, psychiatric disease, cognitive disorder, depression, parkinson's disease, motor dysfunction, genitourinary disorder, bladder dysfunction, overactive bladder, urinary incontinence, neurogenic bladder, psoriasis, itch, vomiting, acne, skin damage, non-ulcer dyspepsia, gastrointestinal dysfunction, functional bowel disease, diarrhea, inflammatory bowel disease, irritable bowel syndrome, interstitial cystitis, sexual dysfunction, drug addiction, alcohol addiction, drug overdose, premature ejaculation, asthma, cough, pulmonary edema, respiratory dysfunction, respiratory depression, functional distension, and movement or secretion disorder, the method comprising administering to a mammal suffering from the disease or condition a therapeutically effective amount of a compound of claim 1.

11. A method of immunomodulation, inhibition or prevention of organ or skin transplant rejection, or treatment of tumors or cancer, comprising administering to a mammal suffering from said disease or condition a therapeutically effective amount of a compound of claim 1.

12. A method of preventing or treating a disease or disorder selected from reperfusion injury, cardiac disorder, pain, functional pain, inflammatory pain, peripherally mediated and neuropathic pain, non-somatic pain, arthritis, psychiatric disease, cognitive disorder, depression, Parkinson's disease, motor dysfunction, genitourinary tract disorders, bladder dysfunction, overactive bladder, urinary incontinence, neurogenic bladder, psoriasis, pruritus, emesis, acne, skin damage, non-ulcer dyspepsia, gastrointestinal dysfunction, functional bowel disease, diarrhea, inflammatory bowel disease, irritable bowel syndrome, interstitial cystitis, sexual dysfunction, drug addiction, alcohol addiction, drug overdose, premature ejaculation, asthma, cough, pulmonary edema, respiratory dysfunction, respiratory depression, functional distension, and movement or secretion disorder, the method comprising administering to a mammal suffering from the disease or condition a therapeutically effective amount of a compound of claim 8.

Technical Field

The present invention relates generally to polycyclic amines useful as opioid receptor modulator-agonists or antagonists, and medicaments comprising the same, which are useful for treating or preventing a variety of centrally-mediated or peripheral indications.

Background

The opiate system consists of three endogenous peptide families (enkephalins, dynorphins and beta-endorphins, respectively) and three homologous receptor families (mu opiate receptor (MOR), Delta Opiate Receptor (DOR) and Kappa Opiate Receptor (KOR), Filizola and Devi, 2013; Cox et al) and pain receptors (NOP) (Lord and Waterfield, 1977; Martin and Thompson, 1976, respectively). The opiate system plays a key role in reward and motivation mechanisms, regulating emotional response and cognition, regulating pain sensation, neuroendocrine physiology, and autonomic function (see Walwyn et al, 2010; Feng et al, 2012). These opioid receptors may also form homodimeric and heterodimeric complexes. These Opioid Receptors (ORs), including monomeric, homodimeric and heterodimeric complexes, signal the kinase cascade and the scaffold of a variety of proteins.

Opioids have been the subject of intensive research since the early isolation of morphine in the 19 th century. Opioids, such as morphine and fentanyl, which are the major analgesics for clinical treatment of pain, which act by activating opioid receptors, are among the most commonly prescribed drugs in the world. Despite their efficacy and practicality, side effects greatly limit their use. These include respiratory depression, constipation, drug tolerance, physical dependence, reward, and addiction.

There is still a clinical need for new opioid receptor modulators for the treatment of pain with little or no side effects. There is also a clinical need for new opioid receptor modulators for cardioprotection and for the treatment of cardiac disorders, pain, functional pain, inflammatory pain, peripherally mediated and neuropathic pain, non-somatic pain, arthritis, psychiatric disorders, cognitive disorders, depression, parkinson's disease, motor dysfunction, genitourinary tract disorders, bladder dysfunction, overactive bladder, urinary incontinence, neurogenic bladder, psoriasis, pruritus, non-ulcer dyspepsia, gastrointestinal dysfunction, functional bowel disease, diarrhea, inflammatory bowel disease, irritable bowel syndrome, interstitial cystitis, sexual dysfunction, drug addiction, alcohol addiction, drug overdose, premature ejaculation, asthma, cough, pulmonary edema, respiratory disorders, respiratory depression, functional expansion, movement disorders or secretion disorders, as well as for immunomodulation, inhibition or prevention of organ or skin transplant rejection, or treating tumors or cancers.

Disclosure of Invention

The present invention provides polycyclic amines, prodrugs and pharmaceutically acceptable salts thereof ("compounds of the invention") that are useful for treating diseases through modulation of opioid receptors.

The compounds of the present invention have the chemical structure of formula I and include pharmaceutically acceptable salts of this structure, such as the hydrochloride salt:

wherein:

a includes substituted or unsubstituted: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and arylalkyl;

y includes substituted or unsubstituted: alkyl, heteroalkyl, cycloalkyl and heterocycloalkyl;

q comprises: substituted or unsubstituted: aryl, heteroaryl and none;

w includes substituted or unsubstituted, saturated or unsaturated: (i) a 4-to 8-membered heterocyclic ring containing an N-substituent as a ring atom; and (ii) bicyclic or heterobicyclic fused rings, wherein each ring is a 4-10 membered ring, and wherein at least one of said rings includes an N-substituent as an atom of said ring;

g comprises a substituted or unsubstituted alkyl group or an N atom;

z comprises substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and none; if Z is null, T is null, but if Z is not null, T is selected from: (i) radicals or atoms H, OH, NH₂、NO₂、-SO₂NH₂Halogen, (ii) substituted or unsubstituted: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

when G is an alkyl group, N is an integer of 1 to 4, and when G is an N atom, N is 1;

R¹and R³Independently selected from H and substituted or unsubstituted: alkyl, heteroalkyl, 3-to 7-membered cycloalkyl, 3-to 7-membered heterocycloalkyl, aryl, and heteroaryl;

m is an integer from 0 to 8, and for R²、R⁴、R⁵And R⁶M may be the same or different, wherein R²、R⁴、R⁵And R⁶Each independently selected from H and substituted or unsubstituted: alkyl, heteroalkyl, 3-to 7-membered cycloalkyl, 3-to 7-membered heterocycloalkyl, and for any R²、R⁴、R⁵And R⁶When m is greater than 1, each such multiple R²，R⁴，R⁵And R⁶The members of the chain may be the same or different; and further provided that when m is greater than 0, R²、R⁴、R⁵And R⁶Always less than or equal to the number of W ring positions available for covalent bonding; and R¹And R³Or R is¹Or R³And Z, or R²And A, or R²And Y together with the groups to which they may be attached optionally form a substituted or unsubstituted 3-to 7-membered ring.

In a second aspect, the invention provides methods for preparing these compounds.

In a third aspect, the invention provides methods of treating diseases by modulating opioid receptors. The compounds are useful for the prevention or treatment of a disease or condition selected from: reperfusion injury, cardiac disorder, pain, functional pain, inflammatory pain, peripherally mediated and neuropathic pain, non-somatic pain, arthritis, psychiatric disease, cognitive disorder, depression, parkinson's disease, motor dysfunction, genitourinary tract disorders, bladder dysfunction, overactive bladder, urinary incontinence, neurogenic bladder, psoriasis, itch, vomiting, acne, skin damage, non-ulcer dyspepsia, gastrointestinal dysfunction, functional bowel disease, diarrhea, inflammatory bowel disease, irritable bowel syndrome, interstitial cystitis, sexual dysfunction, drug addiction, alcohol addiction, drug overdose, premature ejaculation, asthma, cough, pulmonary edema, respiratory dysfunction, respiratory depression, functional distension, and movement or secretory disorder. These compounds are also useful for immunomodulation, inhibition or prevention of organ or skin transplant rejection, or treatment of tumors or cancer. All of these treatments involve administering to the patient an effective amount of a compound of formula I.

In a fourth aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I.

The foregoing and other aspects and embodiments of the invention will become apparent from the following detailed description.

Detailed Description

I. Abbreviations and Definitions

The abbreviations used herein have their conventional meaning in the chemical and biological arts.

When substituents are indicated by their conventional formula written from left to right, they also include chemically identical substituents resulting from writing the structure from right to left, e.g., -CH₂O-is equivalent to-OCH₂-。

Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent means a straight or branched chain or cyclic hydrocarbon group, or combinations thereof, which may be fully saturated, monounsaturated or polyunsaturated, and may include divalent and polyvalent groups, containing the indicated number of carbon atoms (i.e., C)₁-C₁₀Representing 1-10 carbons). Examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologs and isomers thereof, e.g., n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl is alkyl having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, ethenyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2, 4-pentadienyl, 3- (1, 4-pentadienyl), ethynyl, 1-and 3-propynyl, 3-butynyl, and higher homologs and isomers. The term "alkyl" also includes unsubstituted as well as substituted alkyl groups, wherein the substituent of a substituted alkyl group may include any sterically acceptable substituent for which its intended use is compatible with such alkyl compounds. Examples of substituents for substituted alkyl groupsExamples include: halogen (e.g., fluorine, chlorine, bromine, and iodine); an amino group; an amido group; c₁-C₁₀An alkyl group; c₁-C₁₀An alkoxy group; a nitro group; compounds and the like; saturated alkyl groups as well as unsaturated alkyl groups, the latter including groups such as alkenyl-substituted alkyl groups (e.g., allyl, methallyl, propylallyl, butenylmethyl, etc.), alkynyl-substituted alkyl groups, and any other alkyl group containing a sterically acceptable site of unsaturation which is compatible with the alkyl group and which does not preclude the efficacy of the compound for its intended use; and, alkyl groups including a linking moiety or bridging moiety (e.g., heteroatoms such as nitrogen, oxygen, sulfur, and the like).

The term "alkylene" by itself or as part of another substituent refers to a divalent radical derived from an alkane, such as, but not limited to-CH₂CH₂CH₂CH₂And also includes those groups described below as "heteroalkylene". Typically, alkyl (or alkylene) groups contain 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, typically containing 8 or fewer carbon atoms.

The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used herein in their conventional sense and denote those alkyl groups attached to the rest of the molecule through an oxygen, amino or sulfur atom, respectively.

Unless otherwise specified, the term "heteroalkyl," by itself or in combination with other terms, refers to a stable straight or branched chain or cyclic hydrocarbon radical, or combinations thereof, consisting of the indicated number of carbon atoms and at least one heteroatom selected from O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. One or more of the heteroatoms O, N and S and Si may be located at any internal position of the heteroalkyl group, or at the position where the alkyl group is attached to the remainder of the molecule, or at both terminal positions. Examples include, but are not limited to-CH₂-CH₂-O-CH₃,-CH₂-C(＝O)-CH₃,-CH₂-CH₂-CH₂-C(＝O)-O-C(CH₃)-CH₃,-CH₂-CH₂-CH₂-C(＝O)-N-CH(CH₃),-CH₂-CH₂-CH₂-NH-CH₃,-CH₂-CH₂-N(CH₃)-CH₃,-CH₂-S-CH₂-CH₃,-CH₂-CH₂,-S(O)-CH₃,-CH₂-CH₂-S(O)₂-CH₃,-CH＝CH-O-CH₃,-Si(CH₃)₃,-CH₂-CH＝N-OCH₃and-CH ═ CH-N (CH)₃)-CH₃Up to two heteroatoms may be consecutive, e.g. acetamide, -CH₂-NH-OCH₃and-CH₂-O-Si(CH₃)₃. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical of a heteroalkyl group as described above, e.g., -CH₂-CH₂-S-CH₂-CH₂-and-CH₂-S-CH₂-CH₂-NH-CH₂-; and contain heteroatoms (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like) at either or both of the chain ends.

Unless otherwise indicated, the terms "cycloalkyl" and "heterocycloalkyl" by themselves or in combination with other terms denote the cyclic forms of "alkyl" and "heteroalkyl", respectively. Thus, cycloalkyl or heterocycloalkyl groups may include saturated and unsaturated ring bonds. In addition, for heterocycloalkyl, one or more heteroatoms may occupy any position. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, and cycloheptyl. Examples of heterocycloalkyl include, but are not limited to, 1- (1,2,5, 6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, and 2-piperazinyl.

Unless otherwise indicated, the term "halo" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom. In addition, "haloalkyl" includesMonohaloalkyl and polyhaloalkyl. For example, the term "halo (C)₁-C₄) Alkyl "includes, but is not limited to, trifluoromethyl, 2,2, 2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl.

The term "aryl" includes aromatic substituents, including monocyclic and polycyclic; and further includes fused rings and covalently linked rings wherein at least one ring is aromatic, and is further intended to refer to carbocyclic (e.g., phenyl, naphthyl) and heterocyclic aromatic groups (e.g., pyridyl, thienyl, furyl, etc.), and includes unsubstituted as well as substituted aryl groups wherein substituents on a substituted aryl group may include any sterically acceptable substituent that is compatible with such aryl groups and does not preclude the efficacy of the compound for its intended use. Examples of substituents for substituted aryl groups include one or more halogens (e.g., fluorine, chlorine, bromine, and iodine), amino, amido, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, nitro, trifluoromethyl, containing C₁-C₄Hydroxyalkyl groups of alkyl moieties, and the like.

The term "heteroaryl" includes all monocyclic and polycyclic, fused and covalently linked ring structures identical to "aryl" wherein at least one of the aromatic rings contains one or more heteroatoms, such as nitrogen, oxygen and sulfur, wherein the nitrogen and sulfur atoms may be oxidized and the nitrogen atom may be quaternized. Heteroaryl groups may be attached as fused rings or through heteroatoms to the rest of the molecule. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 2-thiazolyl, 3-thiazolyl, 4-thiazolyl, 5-thiazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-imidazolyl, 4-thiazolyl, 5-isoxazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-pyridyl, and the like, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalyl, 5-quinoxalyl, 3-quinolinyl, and 6-quinolinyl. The substituents for each of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

When the term "aryl" is used in combination with other terms (e.g., aryloxy, arylthio, aralkyl), the term "aryl" includes aryl and heteroaryl as defined above. Thus, the term "arylalkyl" includes those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like), including those alkyl groups in which a carbon atom (e.g., methylene) is replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, or 3- (1-naphthyloxy) propyl).

The term "oxo" as used herein refers to an oxygen double bonded to a carbon atom.

Preferred substituents for alkyl and heteroalkyl groups or groups (including those groups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to: aryl, heteroaryl, alkyl, fluoro OR other halogen, -OR ', -O, ═ NR', -N-OR ', -NR' R ', SR', -SiR 'R', -oc (O) R ', -c (O) R', -CO (O)₂R′、-CONR′R″、-OC(O)NR′R″、-NR″C(O)R′、-NR′-C(O)NR″R″′、-NR″C(O)₂R′、-NR-C(NR′R″R″′)＝NR″″、-NR-C(NR'R″)＝NR"'、-S(O)R'、-S(O)₂R′、-S(O)₂NR′R″、-NRSO₂R', -CN and-NO₂。R₁、-N₃、-CH(Ph)₂Fluorine (C)₁-C₄) Alkoxy and fluorine (C)₁-C₄) Alkyl groups in an amount ranging from 0 to (2m '+1), wherein m' is the total number of carbon atoms in such group. R ', R ", R '" and R ' "each preferably independently represent hydrogen, and substituted or unsubstituted: alkyl, heteroalkyl, aryl, alkoxy, thioalkoxy, or aralkyl. For example, when a compound of the invention includes more than one R group, each R group is independently selected, as is each R ', R ", R'" and R "" group when more than one of these groups is present. When R 'and R' are attached to the same nitrogen atom, they may be bonded to the nitrogen atomForming a 5-, 6-or 7-membered ring. For example, -NR' R "is meant to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. The term "substituted" is meant to include groups in which a carbon or N atom is bonded to a group other than a hydrogen group, such as any of the preferred substituents listed herein, and further includes: haloalkyl (e.g., -CF)₃and-CH₂CF₃) And acyl (e.g., -C (O) CH)₃、-C(O)CF₃、-C(O)CH₂OCH₃)。

The substituents of the aryl and heteroaryl groups may preferably be one or more of various groups selected from, but not limited to: aryl OR heteroaryl, including structures forming fused rings OR covalent linkages, as well as alkyl, fluoro OR other halo, -OR ', -O, ═ NR ', -N-OR ', -NR ' R ', -SR ', -SiR ' R ' R ', -OC (O) R ', -C (O) R ', -CO₂R′、-CONR′R″、-OC(O)NR′R″、-NR″C(O)R′、-NR-C(O)NR″R″′、-NR″C(O)₂R′、-NR-C(NR'R″R″′)＝NR″″、-NR-C(NR'R″′)＝NR″′、-S(O)R'、-S(O)₂R'、-S(O)₂NR'R″、-NRSO₂R', -CN and-NO₂、-R'、-N₃、-CH(Ph)₂Fluorine (C)₁-C₄) Alkoxy and fluorine (C)₁-C₄) Alkyl groups, which may be in an amount ranging from 0 to the total number of open valences on the aromatic ring system; and wherein R ', R ", R '" and R ' "each preferably independently represent hydrogen and substituted or unsubstituted: alkyl, heteroalkyl, aryl, alkoxy, thioalkoxy, or aralkyl. For example, when a compound of the invention includes more than one R group, each R group is independently selected, as is each R ', R ", R'" and R "" group when more than one of these groups is present. The term "substituted" is meant to include groups having a carbon or N atom bound to a group other than a hydrogen group, such as any of the preferred substituents listed herein, and further including: haloalkyl (e.g., -CF)₃and-CH₂CF₃) And acyl (e.g., -C (O) CH)₃、-C(O)CF₃、-C(O)CH₂OCH₃)。

Aryl radicalsOr heteroaryl ring substituents include: -T-C (O) - (CRR')_q-U-, wherein T and U are independently-NR-, -O-, -CRR' -or a single bond, and q is an integer from 0 to 3; -A- (CH)₂)_r-B-, wherein A and B are independently-CRR' -, -O-, -NR-, -S (O)₂-、-S(O)₂NR' -or a single bond, and r is an integer of 1 to 4. One of the single bonds of the new ring so formed may be optionally substituted by a double bond. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally substituted by a group of formula- (CRR')_s-X-(CR″R″′)_d-wherein S and d are independently integers from 0 to 3, and X is-O-, -NR' -, -S (O)₂-or-S (O)₂NR' -. The substituents R, R 'and R' are independently selected from hydrogen or substituted or unsubstituted (C)₁-C₆) An alkyl group.

As used herein, the term "heterocycle" includes heterocycloalkyl and heteroaryl rings.

As used herein, the term "heterobicyclic" includes two heterocycloalkyl or two heteroaryl rings, as well as bicyclic rings in which one ring is heterocycloalkyl and the other ring is heteroaryl, and bicyclic rings in which one ring is heterocycloalkyl or heteroaryl and the other ring is cycloalkyl or aryl.

As used herein, the term "heteroatom" includes oxygen (O), nitrogen (N), sulfur (S), and silicon (Si). The term "plurality" as used herein means at least 2. For example, a polyvalent metal ion is a metal ion having a valence of at least 2.

The term "free" means that no group or moiety is present at the indicated position (although hydrogen may be present where an adjacent group is a group).

"moiety" refers to a group of a molecule that is attached to another moiety.

Symbol

Whether displayed as a bond or perpendicular to a bond, indicates the point at which the displayed portion is attached to the rest of the molecule.

Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms (including hydrated forms). In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous form. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

The compound of the present invention or a pharmaceutically acceptable salt thereof may have an asymmetric carbon atom or double bond in its structure. Thus, the compounds of the present invention and their pharmaceutically acceptable salts may exist as single stereoisomers, racemates and mixtures of enantiomers, diastereomers and geometric isomers. All such single stereoisomers, racemates and mixtures thereof are included within the scope of the present invention. The absolute configuration of certain carbon atoms within a compound is represented by the appropriate absolute descriptor R or S, if known.

Tautomeric forms of the compounds of formula (I) include those compounds of formula (I) wherein, for example, an enol group is converted to a keto group (keto-enol tautomerism).

The compounds of formula (I) prepared in the methods described below may be synthesized as racemic mixtures of enantiomers, which may be separated according to resolution methods known in the art. The racemic compounds of formula (I) can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Subsequently, the diastereomeric salt forms are separated, for example by selective or fractional crystallization, and the enantiomers are liberated therefrom by means of a base. Another method for separating enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. The pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereoselectively. Preferably, if a particular stereoisomer is desired, the compound will be synthesized by stereoselective methods of preparation. These processes preferably use pure enantiomeric starting materials.

The compounds of the invention may also be used in the construction of one or more of the atoms of such compoundsThe atoms contain unnatural proportions of atomic isotopes. For example, the compounds may be treated with radioactive isotopes such as tritium (3H), iodine-125 (¹²⁵I) Or carbon-14 (¹⁴C) And (4) radioactive labeling. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

As used herein, "therapeutic" includes prophylaxis, treatment and/or prophylaxis, in humans as well as other animals.

"pharmaceutically or therapeutically effective dose or amount" refers to a dosage level sufficient to induce a desired biological result. The result may be a reduction in the signs, symptoms, or causes of the disease or any other alteration of a desired biological system. The precise dosage will vary depending on a variety of factors including, but not limited to, the age and size of the subject, the disease being treated and the treatment being received.

A "host" or "patient" or "subject" is a living mammal, human or animal in need of treatment. "host," "patient" or "subject" generally refers to the recipient of a treatment performed according to the methods of the present invention. It should be noted that the invention described herein can be used in veterinary as well as human applications, and the term "host" should not be construed in a limiting manner. In the case of veterinary applications, the dosage range can be determined as described below, taking into account the weight of the animal.

As used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic agent is administered, and includes, but is not limited to, sterile liquids such as water and oil.

The term "pharmaceutically acceptable salt" is meant to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents present on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by reacting the neutral form of the compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts may be obtained by reacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as those derived from acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like, which are relatively nontoxic organic acids. Also included are Salts of amino acids such as arginine, and Salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into base or acid addition salts.

The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

In addition to salt forms, the present invention also provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when a prodrug is placed in a transdermal patch with a suitable enzyme or chemical agent, the prodrug can be slowly converted to a compound of the invention. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, they may be bioavailable by oral administration whereas the parent drug may not. The prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug. A variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. One non-limiting example of a prodrug, a compound of the invention, is administered as an ester ("prodrug") and then metabolically hydrolyzed to the carboxylic acid, the active entity. Other examples include peptidyl derivatives of the compounds of the invention. Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous form. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

A "pharmaceutical composition" is a formulation comprising a disclosed compound in a form suitable for administration to a subject. The pharmaceutical compositions of the present invention are preferably formulated in a form compatible with their intended route of administration. Examples of routes of administration include, but are not limited to, oral and parenteral administration, such as intravenous, intradermal, subcutaneous, inhalation, topical, transdermal, transmucosal and rectal administration.

Opioid receptor modulators

The compounds of the invention have the structure as in formula I above.

One broad aspect of the invention relates to compounds, including inter alia, such compounds and methods of making and using the same.

The present invention relates to compounds of formula I and pharmaceutical compositions comprising them, which are useful as opioid receptor modulator-agonists or antagonists and which have particular biological activities and properties that render them useful as therapeutic agents for the treatment or prevention of a variety of physiological and pathological conditions, including a variety of centrally-mediated or peripherally-mediated indications, such as reperfusion injury, cardiac disorders, pain, functional pain, inflammatory pain, peripherally-mediated and neuropathic pain, non-somatic pain, arthritis, psychiatric disorders, cognitive disorders, depression, Parkinson's disease, motor dysfunction, genitourinary tract disorders, bladder dysfunction, overactive bladder, urinary incontinence, neurogenic bladder, psoriasis, pruritus, emesis, acne, skin lesions, non-ulcer dyspepsia, gastrointestinal dysfunction, functional bowel disease, diarrhea, inflammatory bowel disease, irritable bowel syndrome, interstitial cystitis, sexual dysfunction, drug addiction, alcohol addiction, drug overdose, premature ejaculation, asthma, cough, pulmonary edema, a respiratory function disorder, respiratory depression, functional distension, a movement disorder or a secretion disorder, and for immunomodulation, inhibition or prevention of organ or skin transplant rejection, or treatment of tumors or cancers.

In particularly preferred methods of the invention, the treatment or prevention of central and peripheral pain, migraine, depression and Parkinson's disease, overactive bladder or urinary incontinence, diarrhea, irritable bowel syndrome and gastrointestinal disorders is effected by administering to a subject in need of such treatment or prevention an effective amount of a compound of formula (I) or a pharmaceutically acceptable ester or salt thereof.

Examples of pharmaceutically acceptable salts of compounds of formula (1) include salts derived from suitable bases, for example alkali metals (e.g. sodium, potassium), alkaline earth metals (e.g. calcium, magnesium), ammonium and NR'₄ ⁺(wherein R' is C₁-C₄Alkyl) salts. Pharmaceutically acceptable salts of compounds of formula (1) having an amino group include: salts of organic carboxylic acids such as acetic acid, lactic acid, tartaric acid, malic acid, lactobionic acid, fumaric acid and succinic acid; salts of organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid and p-toluenesulfonic acid; and salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and sulfamic acid. Pharmaceutically acceptable salts of compounds of formula (1) having a hydroxy group are prepared by reacting the anion of these compounds with a suitable cation such as Na⁺，NH₄ ⁺Or NR'₄ ⁺(wherein R' is, for example, C)_1-4Alkyl) groups.

The compounds of formula (1) have utility as exogenous receptor binding or complexing compounds, and may be used to bind to opioid receptors. In addition, the compounds can be used as couplers in agonist/antagonist pairs for transduction assays of neurotransmitter function in relevant cellular or differentiated tissue systems, and for specific applications for receptor assays, differential binding, and cellular, histological and physical monitoring and evaluation purposes.

The compounds of formula (1) may be administered for therapeutic intervention in a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier. The present invention contemplates any manner and/or mode of administration of the compositions of the present invention.

The compound of the above general formula (1) exhibits binding selectivity to a receptor. Binding selectivity depends on the structure and stereospecificity of the particular compound of formula (1), which may exhibit binding to a receptor selected from the group consisting of delta receptors, mu receptors, kappa receptors, nociceptive receptors, and combinations of these receptors.

The compounds contemplated by the present invention include the compounds of formula (1) themselves, as well as physiologically functional derivatives thereof. "physiologically functional derivatives" include pharmaceutically acceptable: salts, ethers, esters of compounds of formula (1); or, a salt of an ether or ester of a compound of formula (1); or, any other compound capable of providing (directly or indirectly) said compound of formula (1) or an active metabolite or residue thereof upon administration to a recipient. Phenol C₁-C₆Alkyl ethers are a subset of physiologically functional derivatives of the compounds of formula (1).

The compounds of the present invention can be readily synthesized within the skill of the art and in accordance with the illustrative synthetic examples set forth below.

When used in pharmaceutical or diagnostic applications, the compounds of the invention are preferably prepared as racemic mixtures or substantially pure enantiomeric forms having an enantiomeric purity of at least 90% Enantiomeric Excess (EE), preferably at least 95% EE, more preferably at least 98% EE, and most preferably at least 99% EE. Enantiomeric excess values provide a quantitative measure of the excess of the percent of the major isomer relative to the percent of the minor isomer present therewith, and can be readily determined by suitable methods well known and established in the art, such as chiral High Pressure Liquid Chromatography (HPLC), chiral Gas Chromatography (GC), Nuclear Magnetic Resonance (NMR) using chiral transfer reagents, and the like.

The subject treated by the methods of the invention is preferably a human subject, but also includes non-human mammals and other animals (e.g., birds, dogs, cats, cattle, horses).

Depending on the particular condition to be treated, the subject may be administered the compound of formula (1) at any suitable therapeutically effective and safe dose, as readily determined by one of skill in the art, and extrapolated without undue experimentation from the animal dosages set forth in the examples herein. In vitro assays for agonist/antagonist activity, such as receptor binding affinity assays, and inhibition of electrostimulation muscle twitch assays, the compounds of the present invention exhibit potency in the nanomolar to micromolar concentration range, depending on the particular compound used.

In general, although effective dosages of the compounds of the invention for therapeutic use may vary widely in the broad practice of the invention, depending upon the particular application, disorder or disease state involved, as readily determined by one of skill in the art, for each of the relevant compositions described herein, and to achieve the therapeutic benefits of each of the disorders described herein, suitable therapeutic dosages of the compounds of the invention will be in the range of from 10 micrograms (μ g) to 100 milligrams (mg) per kilogram body weight of the recipient per day, preferably in the range of from 50 μ g to 75mg per kilogram body weight per day, and most preferably in the range of from 100 μ g to 50mg per kilogram body weight per day. The desired dose is preferably expressed as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example containing from 10 μ g to 1000mg, preferably from 50 μ g to 500mg, more preferably from 50 μ g to 250mg, and most preferably from 50 μ g to 10mg of active ingredient per unit dosage form. Alternatively, the dosage may be administered as a continuous infusion if the condition of the recipient requires it.

The mode of administration and dosage form will affect the therapeutic amount of the compound that is desired and effective for a given therapeutic application.

For example, for the same active ingredient, the dosage for oral administration is typically at least twice, e.g., 2-10 times, the dosage level used in the parenteral method of administration. In oral administration, the dosage levels of the delta receptor binding compounds of the invention may be on the order of 5-200mg/70kg body weight/day. In tablet dosage forms, typical active agent dosage levels are on the order of 10-100mg per tablet.

The compounds of formula (1) may be administered as such, as well as in the form of pharmaceutically acceptable esters, salts and ethers, as well as other physiologically functional derivatives of these compounds.

The invention also contemplates pharmaceutical compositions for veterinary and human medical use comprising one or more compounds of the invention as active agents.

In such pharmaceutical compositions, the active agent is preferably used together with one or more of its pharmaceutically acceptable carriers and optionally any other therapeutic ingredients. The carrier is preferably compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The active agent is preferably present in a pharmaceutically acceptable amount effective to achieve the desired pharmacological effect.

Formulations include those suitable for parenteral as well as non-parenteral administration, specific modes of administration including oral, rectal, topical, sublingual, mucosal, transdermal, nasal, ocular, subcutaneous, intramuscular, intravenous, transdermal, spinal, intrathecal, intra-articular, intra-arterial, subarachnoid, bronchial, lymphatic and intra-uterine administration. Formulations suitable for oral administration are preferred.

When the active agent is used in a formulation comprising a liquid solution, the formulation may advantageously be administered parenterally. When the active agent is used in a liquid suspension formulation or as a powder in a biocompatible carrier formulation, the formulation may advantageously be administered orally, rectally or bronchially.

When the active agent is used directly in the form of a powdered solid, the active agent may advantageously be administered orally. Alternatively, the powder may be administered bronchially by spraying the powder in a carrier gas to form a gaseous dispersion of the powder which is inhaled by the patient from a breathing circuit comprising a suitable nebulizer device.

In some applications, it may be advantageous to use the active agent in a "vectorized" form, for example by encapsulating it in a liposome or other encapsulating medium, or by immobilizing it on a suitable biomolecule, for example selected from proteins, lipoproteins, glycoproteins and polysaccharides, for example by covalent bonding, chelation or association coordination.

Formulations comprising the active agents of the present invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods typically include the step of bringing into association the active compound with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers, finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administration may be presented as discrete units, such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active ingredient in powder or granular form; or suspensions in aqueous or non-aqueous liquids, such as syrups, elixirs, emulsions or inhalants.

Tablets may be prepared by compression or moulding, optionally together with one or more accessory ingredients. Compressed tablets may be prepared by compression in a suitable machine, in which the active compound is in a free-flowing form such as a powder or granules, optionally mixed with a binder, disintegrant, lubricant, inert compound, surfactant or release agent. Molded tablets, which consist of a mixture of the active compound in powder form with a suitable carrier, can be prepared by molding in a suitable machine.

Syrups may be prepared by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which any auxiliary ingredient may also be added. Such adjunct ingredients may include flavouring agents, suitable preservatives, agents to retard the crystallisation of the sugar, and agents to increase the solubility of any other ingredient, for example a polyhydric alcohol, for example glycerol or sorbitol.

Formulations suitable for parenteral administration conveniently comprise sterile aqueous preparations of the active compound which are preferably isotonic with the blood of the recipient (e.g. physiological saline solution). Such formulations may include suspending and thickening agents as well as liposomes or other microparticulate systems designed to target the compound to blood components or one or more organs. The formulations may be presented in unit dose or multi-dose form.

Nasal spray formulations comprise a purified aqueous solution of the active compound together with a preservative and an isotonic agent. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal mucosa.

Formulations for rectal administration may be presented as a suppository with a suitable carrier, for example, cocoa butter, hydrogenated fats or hydrogenated fatty carboxylic acids.

Ophthalmic formulations are prepared by methods similar to nasal spray formulations, except that the pH and isotonicity factor are preferably adjusted to match the pH and isotonicity factor of the eye.

Topical formulations comprise the active compound dissolved or suspended in one or more media, such as mineral oil, petroleum, polyhydric alcohols or other bases used in topical pharmaceutical formulations.

Transdermal formulations may be prepared by incorporating the active agent in a thixotropic or gel-like carrier such as a cellulosic medium (e.g., methylcellulose or hydroxyethylcellulose) and then packaging the resulting formulation in a transdermal device suitable for immobilization in contact with the dermis of the wearer's skin.

In addition to the above ingredients, the formulations of the present invention may also contain one or more auxiliary ingredients selected from diluents, buffers, flavoring agents, binders, disintegrants, surfactants, thickeners, lubricants, preservatives (including antioxidants), and the like.

The disease state or physiological condition in which such therapeutic intervention is implicated may be of any of the types or classes described above, for example, centrally mediated disorders; pain, depression, drug addiction and drug dependence, alcohol addiction; and peripherally mediated neuropathic pain, cough, pulmonary edema, gastrointestinal disorders, arthritis, psoriasis, asthma, inflammatory bowel disease, respiratory functional disorders, functional bowel disease, irritable bowel syndrome, diarrhea, functional distension, pain (e.g., functional pain, wound pain, etc.), non-ulcer-derived dyspepsia, genitourinary tract disorders, premature ejaculation, overactive alopecia, urinary incontinence, organ transplant rejection, skin transplant rejection, heart disease, reperfusion injury, vomiting, acne, and skin injury.

The invention is further illustrated by the following non-limiting preparation schemes and other examples.

Preparation of opioid receptor modulators

The following exemplary schemes illustrate methods of making the compounds of the present invention. These methods are not limited to the preparation of the listed compounds, but can also be used to prepare other substrates. The compounds of the present invention may also be prepared by methods not specifically illustrated in the schemes. The compounds can be prepared using readily available starting materials or known intermediates.

Scheme 1

Compounds wherein "a" of formula I is an alkyl or heteroalkyl moiety are synthesized as shown in scheme 1. The synthesis of compounds 1-6 is illustrated.

Wherein for scheme I above, X is selected from: cl, Br, I, p-toluenesulfonyl (Tos), methanesulfonyl (Ms) and trifluoromethanesulfonyl (Tf).

In scheme 1, the substituted cyclic ester 1-1 is deprotonated in the presence of a strong base (e.g., LDA, LHMDS, etc.), and then alkylated to yield 1-2 a. Reduction of 1-2a followed by alkylation gives ethers 1-4. Deprotection of the Boc group of 1-4 is carried out in the presence of an acid (e.g., TFA, HCl, etc.). Reductive amination of 1-5 with the appropriate aldehyde or ketone 1-5a or alkylation of 1-5 with 1-5b under basic conditions gives 1-6. Having a radical of formula (I) with R¹Compounds of different structural moieties are exemplified by the synthesis of intermediates such as 1-2b, 1-2c or 1-2 d. 1-1 is reacted with a suitable ketone or aldehyde 1-7 to give intermediate 1-2 b. Activation of the hydroxyl group of 1-2b using methanesulfonyl chloride followed by elimination in the presence of a base (e.g., DBU, etc.) yields unsaturated intermediate 1-2 c. Hydrogenation of 1-2c to give intermediates 1-2 d.

Scheme 2:

compounds in which "a" of formula I is a cyclic alkyl or cyclic heteroalkyl moiety are synthesized as shown in scheme 2. The synthesis of compounds 2-6 serves as an example.

The oxidation of 1-3 to 2-1 is carried out by Swern oxidation or other oxidizing agents such as Dess-Martin periodic acid compounds (periodianes) and the like. The aldehyde 2-1 undergoes a Grignard reaction with an unsaturated or saturated Grignard reagent followed by alkylation with an unsaturated or saturated alkylating reagent under basic conditions to give 2-3. 2-3 ring-closing metathesis (RCM) with a catalyst such as Grubbs ruthenium-carbene complex or the like produces an unsaturated oxygen-containing heterocycle 2-4 or produces a saturated oxygen-containing heterocycle 2-4 after hydrogenation. Alternatively, the synthesis of 2-4 is accomplished by Grignard reaction of 2-1 with 2-1a or 2-1b followed by deprotection of intermediate 2-7 or hydroboration of the double bond of intermediate 2-9 to give the corresponding diol 2-8. Diol 2-8 is converted to 2-4 by intramolecular cyclization under Mitsunobu reaction conditions or displacement of the corresponding mesylate, tosylate, etc.

Finally, 2-6 was synthesized from 2-4 using the same method as for the transformation of 1-4 to 1-6 in scheme 1.

Scheme 3:

compounds wherein "A" of formula I is a heteroaryl moiety are synthesized as shown in scheme 3 and exemplified by the synthesis of 3-8.

Cyano intermediates 3-3 and ester intermediates 3-5 were prepared from substituted 3-2 by cyanation and 3-4 by alkylation as described in scheme 1. The cyano group of 3-3 and the ester group of 3-5 are converted to heterocycles such as imidazole, thiazole, thiadiazole, oxadiazole 3-6(3-6a, 3-6b, 3-6c and 3-6d) and the like, by corresponding intermediates such as amide, thioamide, hydrazide, thiohydrazide or N-hydroxy-imidoamide, using the general methods exemplified in scheme 3. The conversion of 3-6 to 3-8 was achieved using the method shown in scheme 1.

Scheme 4:

compounds wherein "A" of formula I is a heteroalkyl moiety are synthesized as shown in scheme 4 and exemplified by the synthesis of 4-6.

Suitable substituted cyclic amides 4-3 are prepared from the corresponding esters 4-1 by hydrolysis using a base such as NaOH, LiOH, KOH, etc., followed by coupling with an amine in the presence of a coupling agent (e.g., EDCI/HOBt, DCC, HATU, etc.). Using BH₃Or LiAlH₄Reduction of 4-3 followed by deprotection of the Boc group of 4-4 and alkylation of 4-5 as described in scheme 1 gives compounds 4-6.

Scheme 5:

compounds were synthesized in which Y and Q of formula I are specific moieties, as shown in scheme 5.

Reduction of the cyano group to the aldehyde 5-1 followed by Wittig reaction with a quaternary phosphonium salt such as 5-1a yields the compound 5-2. The double bond of 5-2 is hydrogenated, and then 5-2 is deprotected, or alkylated after deprotection to obtain unsaturated or saturated compound 5-8. The quaternary phosphonium salt 5-1a is prepared from the appropriate bromide 5-9. The appropriate bromide 5-9 is converted to the corresponding aldehyde 5-10, which is then reduced with a suitable reducing agent such as NaBH4 or the like to provide the alcohol 5-11. Halogenation of the alcohol 5-11 followed by treatment with PPh3 affords the quaternary phosphonium salt 5-1 a.

Scheme 6:

compounds wherein Y and Q of formula I are other moieties than those of scheme 5 are synthesized as shown in scheme 6.

Alcohol 2-2 is oxidized with an oxidizing agent such as Dess-Martin periodic acid compound, PCC, etc. to form ketone 6-1. Deprotection of the Boc group of 6-1 followed by alkylation gives 6-3.

Scheme 7:

compounds were synthesized in which Z and T of formula I are specific moieties, as shown in scheme 7.

Starting material 7-1 is a group of intermediates prepared according to schemes 1 to 6. 7-1 aryl is substituted or unsubstituted aryl, such as phenyl, thiazolyl, thienyl, furyl, imidazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl. R₄Are functional groups such as Br, I, CN, COOH, COOEt, boronic acid. R₄To R₆The conversion of (a) is effected by Suzuki coupling of boronic acids with Br or I, or by cyclization of hydrazides of esters with acids, or cyclization of N-hydroxy-imide amides with acid chlorides.

Scheme 8:

scheme 8 illustrates one of the methods for synthesizing stereoisomers. Furthermore, the synthesis of two enantiomerically pure isomers is also achieved by chiral separation via chiral HPLC, chiral resolution or column chromatography.

In scheme 8, the ester 8-2 prepared according to scheme 1 is hydrolyzed to the acid 8-3 using an inorganic base such as LiOH, NaOH, KOH, etc. Acid 8-3 is activated to its corresponding acid chloride or mixed anhydride and then reacted with a lithiated chiral auxiliary salt to give a mixture of diastereomers 8-4 and 8-5. Separation of the diastereomeric mixture provides the individual enantiomers 8-4 and 8-5.

The enantiomerically pure intermediates such as 8-4 and 8-5 were further converted to various key intermediates such as 8-8 and 8-10 in enantiomerically pure form using the procedures shown in schemes 1-7. Some examples are illustrated in scheme 9 and scheme 10 below.

Scheme 9:

scheme 9 shows an example of the synthesis of enantiomerically pure compound 9-8 starting from 8-4.

Using NaBH₄The enantiomerically pure intermediate 8-4 described in scheme 8 was reduced to the chiral alcohol 9-1. The conversion of alcohols 9-1 to 9-8 was carried out according to the methods described in schemes 1 to 5.

Scheme 10:

scheme 10 shows an example of the synthesis of enantiomerically pure compound 10-8 starting from 8-5.

Enantiomerically pure compound 10-8 was synthesized according to the procedure described in scheme 9 starting from 8-5.

Scheme 11:

scheme 11 shows an example of the synthesis of enantiomeric intermediates 10-3 and 9-1 by chiral resolution starting from 8-3.

The enantiomeric intermediates 10-3 and 9-1 were synthesized according to the methods described in schemes 9 and 10, starting from 8-3.

Compound preparation (composition)

For preparing pharmaceutical compositions from the compounds of the present invention, the pharmaceutically acceptable carrier may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in admixture with the finely divided active component. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

Powders and tablets preferably contain 5% or 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "formulation" is intended to include a formulation of an active compound with an encapsulating material as a carrier, which encapsulating material provides a capsule in which the active ingredient, with or without other carriers, is surrounded by a carrier with which it is associated. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid dosage forms suitable for oral administration.

To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is homogeneously dispersed therein, for example by stirring. The molten homogeneous mixture is then poured into a suitably sized mold, allowed to cool, and thereby solidified.

Liquid form preparations include solutions, suspensions and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, the liquid formulation can be formulated in a solution in the form of an aqueous solution of polyethylene glycol.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable coloring, flavoring, stabilizing and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, for example, natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. In addition to the active ingredients, these preparations may contain coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickening agents, solubilizing agents, and the like.

The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Moreover, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

The amount of active ingredient in a unit dose formulation may be varied or adjusted to provide a pharmaceutically acceptable dose of the active ingredient.

Examples

The following examples are illustrative of the methods and compositions described herein and are not limiting. Other suitable variations and modifications of the various conditions and parameters normally encountered in treatment and which are obvious to those skilled in the art are within the spirit and scope of the compounds and methods described herein.

In the following examples, temperatures are given in degrees Celsius (. degree. C.) unless otherwise indicated; the operation is carried out at room or ambient temperature "RT" or "RT" (typically in the range of about 18-25 ℃); evaporation of the solvent is carried out using a rotary evaporator under reduced pressure (typically 4.5-30mmHg) with a bath temperature of up to 60 ℃; the course of the reaction is typically followed by Thin Layer Chromatography (TLC), and the reaction time is provided for illustration only; the melting point is not corrected; the product showed satisfactory¹H-NMR and/or microanalysis data; the yields provided are for illustration only; and the following conventional abbreviations are also used: mp (melting point), L (L), mL (mL), mmol (mmol), g (g), mg (mg), min (min) and h (h).