U.S. patent application number 15/496160 was filed with the patent office on 2017-08-10 for 3-(4'-substituted)-benzyl-ether derivatives of pregnenolone.
The applicant listed for this patent is INSERM (Institut National de la Sante et de la Recherche Medicale), SC BELENOS, Universite de Bordeaux. Invention is credited to Sandy Fabre, Francois-Xavier Felpin, Pier Vincenzo Piazza, Jean-Michel Revest, Monique Vallee.
Application Number | 20170226148 15/496160 |
Document ID | / |
Family ID | 47278185 |
Filed Date | 2017-08-10 |
United States Patent
Application |
20170226148 |
Kind Code |
A1 |
Piazza; Pier Vincenzo ; et
al. |
August 10, 2017 |
3-(4'-SUBSTITUTED)-BENZYL-ETHER DERIVATIVES OF PREGNENOLONE
Abstract
The invention relates to a compound of Formula (I), or a
pharmaceutically acceptable salt thereof: wherein R1 is C1-8 alkyl,
C1-8 alkoxy, CN, NO.sub.2, amino, COOH, COOCH.sub.3, OH, N.sub.3,
or halogen and R2 is H, OH, C1-8 alkyl, C1-8 alkoxy, C2-C6 alkenyl,
halogen, Bn-O--, Bn- optionally substituted, or Ph- optionally
substituted. ##STR00001##
Inventors: |
Piazza; Pier Vincenzo;
(Bordeaux, FR) ; Vallee; Monique; (Bordeaux,
FR) ; Felpin; Francois-Xavier; (Nantes, FR) ;
Revest; Jean-Michel; (Bordeaux, FR) ; Fabre;
Sandy; (Cenon, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
INSERM (Institut National de la Sante et de la Recherche
Medicale)
SC BELENOS
Universite de Bordeaux |
Paris
Bordeaux
Bordeaux |
|
FR
FR
FR |
|
|
Family ID: |
47278185 |
Appl. No.: |
15/496160 |
Filed: |
April 25, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14443778 |
May 19, 2015 |
|
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PCT/EP2013/074886 |
Nov 27, 2013 |
|
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15496160 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 1/16 20180101; A61P
19/10 20180101; A61P 15/08 20180101; A61P 13/10 20180101; C07J
7/0045 20130101; C07J 41/005 20130101; A61P 25/00 20180101; A61P
13/12 20180101; A61P 1/00 20180101; A61P 1/06 20180101; A61P 27/06
20180101; A61P 43/00 20180101; A61P 29/00 20180101; C07J 7/002
20130101; A61P 35/00 20180101; A61P 39/02 20180101; A61P 25/04
20180101; A61P 25/30 20180101; A61P 3/00 20180101; A61P 25/28
20180101; A61P 3/04 20180101; A61P 37/06 20180101; A61P 17/00
20180101; A61P 29/02 20180101; C07J 41/0094 20130101; A61P 9/00
20180101 |
International
Class: |
C07J 7/00 20060101
C07J007/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 28, 2012 |
EP |
12194704.8 |
Claims
1. A compound of Formula I or a pharmaceutically acceptable salt
thereof, ##STR00034## wherein: R1 is: C1-8 alkyl, C1-8 alkoxy, CN,
NO.sub.2, amino, COOH, COOCH.sub.3 OH, N.sub.3, or halogen and R2
is: H, OH, C1-8 alkyl, C1-8 alkoxy, C2-C6 alkenyl, halogen,
Bn-O-Bn- optionally substituted with C1-8 alkyl, C1-8 alkoxy, CN,
NO.sub.2, amino, COOH or halogen or Ph- optionally substituted with
C1-8 alkyl, C1-8 alkoxy, CN, NO.sub.2, amino, COOH or halogen.
2. The compound according to claim 1 wherein R2 is in a
position.
3. The compound according to claim 1 wherein R1 is OH, C1-8 alkyl,
C1-8 alkoxy or halogen.
4. The compound according to claim 3 wherein R1 is OH, methyl,
ethyl, methoxy, ethoxy, methylcarboxy, Cl, Br, F or cyano.
5. The compound according to claim 1 wherein R2 is H, OH, C1-8
alkyl, C1-8 alkoxy, C1-8 alkenyl or Bn.
6. The compound according to claim 5 wherein R2 is H, OH, methyl,
ethyl, methoxy, ethoxy, allyl or Bn.
7. The compound according to claim 1 is:
3-(p-hydroxybenzyloxy)-pregnenolone,
3-(p-methylbenzyloxy)-pregnenolone,
3-(p-ethylbenzyloxy)-pregnenolone,
3-(p-methoxybenzyloxy)-pregnenolone,
3-(p-ethoxybenzyloxy)-pregnenolone,
3-(p-methylcarboxybenzyloxy)-pregnenolone,
3-(p-fluorobenzyloxy)-pregnenolone,
3-(p-chlorobenzyloxy)-pregnenolone,
3-(p-bromobenzyloxy)-pregnenolone,
3-(p-cyanobenzyloxy)-pregnenolone,
17-hydroxy-3-(p-hydroxybenzyloxy)-pregnenolone,
17-hydroxy-3-(p-methylbenzyloxy)-pregnenolone,
3-(p-ethylbenzyloxy)-17-hydroxy-pregnenolone,
17-hydroxy-3-(p-methoxybenzyloxy)-pregnenolone,
3-(p-ethoxybenzyloxy)-17-hydroxy-pregnenolone,
17-hydroxy-3-(p-methylcarboxybenzyloxy)-pregnenolone,
3-(p-fluorobenzyloxy)-17-hydroxy-pregnenolone,
3-(p-chlorobenzyloxy)-17-hydroxy-pregnenolone,
3-(p-bromobenzyloxy)-17-hydroxy-pregnenolone,
3-(p-cyanobenzyloxy)-17-hydroxy-pregnenolone,
3-(p-hydroxybenzyloxy)-17-methyl-pregnenolone,
17-methyl-3-(p-methylbenzyloxy)-pregnenolone,
3-(p-ethylbenzyloxy)-17-methyl-pregnenolone, 3-(p-methoxybenzyl
oxy)-17-methyl-pregnenolone,
3-(p-ethoxybenzyloxy)-17-methyl-pregnenolone,
17-methyl-3-(p-methylcarboxybenzyloxy)-pregnenolone,
3-(p-fluorobenzyloxy)-17-methyl-pregnenolone,
3-(p-chlorobenzyloxy)-17-methyl-pregnenolone,
3-(p-bromobenzyloxy)-17-methyl-pregnenolone,
3-(p-cyanobenzyloxy)-17-methyl-pregnenolone,
17-ethyl-3-(p-hydroxybenzyloxy)-pregnenolone,
17-ethyl-3-(p-methylbenzyloxy)-pregnenolone,
17-ethyl-3-(p-ethylbenzyloxy)-pregnenolone,
17-ethyl-3-(p-methoxybenzyloxy)-pregnenolone,
3-(p-ethoxybenzyloxy)-17-ethyl-pregnenolone,
17-ethyl-3-(p-methylcarboxybenzyloxy)-pregnenolone,
17-ethyl-3-(p-fluorobenzyloxy)-pregnenolone,
3-(p-chlorobenzyloxy)-17-ethyl-pregnenolone,
3-(p-bromobenzyloxy)-17-ethyl-pregnenolone,
3-(p-cyanobenzyloxy)-17-ethyl-pregnenolone,
3-(p-hydroxybenzyloxy)-17-methoxy-pregnenolone,
17-methoxy-3-(p-methylbenzyloxy)-pregnenolone,
3-(p-ethylbenzyloxy)-17-methoxy-pregnenolone,
17-methoxy-3-(p-methoxybenzyloxy)-pregnenolone,
3-(p-ethoxybenzyloxy)-17-methoxy-pregnenolone,
17-methoxy-3-(p-methylcarboxybenzyloxy)-pregnenolone,
3-(p-fluorobenzyloxy)-17-methoxy-pregnenolone,
3-(p-chlorobenzyloxy)-17-methoxy-pregnenolone,
3-(p-bromobenzyloxy)-17-methoxy-pregnenolone,
3-(p-cyanobenzyloxy)-17-methoxy-pregnenolone,
17-ethoxy-3-(p-hydroxybenzyloxy)-pregnenolone,
17-ethoxy-3-(p-methylbenzyloxy)-pregnenolone,
17-ethoxy-3-(p-ethylbenzyloxy)-pregnenolone,
17-ethoxy-3-(p-methoxybenzyloxy)-pregnenolone,
17-ethoxy-3-(p-ethoxybenzyloxy)-pregnenolone,
17-ethoxy-3-(p-methylcarboxybenzyloxy)-pregnenolone,
17-ethoxy-3-(p-fluorobenzyloxy)-pregnenolone,
3-(p-chlorobenzyloxy)-17-ethoxy-pregnenolone,
3-(p-bromobenzyloxy)-17-ethoxy-pregnenolone,
3-(p-cyanobenzyloxy)-17-ethoxy-pregnenolone,
17-allyl-3-(p-hydroxybenzyloxy)-pregnenolone,
17-allyl-3-(p-methylbenzyloxy)-pregnenolone,
17-allyl-3-(p-ethylbenzyloxy)-pregnenolone,
17-allyl-3-(p-methoxybenzyloxy)-pregnenolone,
17-allyl-3-(p-ethoxybenzyloxy)-pregnenolone,
17-allyl-3-(p-methylcarboxybenzyloxy)-pregnenolone,
17-allyl-3-(p-fluorobenzyloxy)-pregnenolone,
17-allyl-3-(p-chlorobenzyloxy)-pregnenolone,
17-allyl-3-(p-bromobenzyloxy)-pregnenolone,
17-allyl-3-(p-cyanobenzyloxy)-pregnenolone,
17-benzyl-3-(p-hydroxybenzyloxy)-pregnenolone,
17-benzyl-3-(p-methylbenzyloxy)-pregnenolone,
17-benzyl-3-(p-ethylbenzyloxy)-pregnenolone,
17-benzyl-3-(p-methoxybenzyloxy)-pregnenolone,
17-benzyl-3-(p-ethoxybenzyloxy)-pregnenolone,
17-benzyl-3-(p-methylcarboxybenzyloxy)-pregnenolone,
17-benzyl-3-(p-fluorobenzyloxy)-pregnenolone,
17-benzyl-3-(p-chlorobenzyloxy)-pregnenolone,
17-benzyl-3-(p-bromobenzyloxy)-pregnenolone or
17-benzyl-3-(p-cyanobenzyloxy)-pregnenolone.
8. The compound according to claim 1 which is selected from the
group consisting of
3.beta.-(p-Methoxybenzyloxy)-17.alpha.-methyl-pregnenolone,
17-benzyl-3-(p-methoxybenzyloxy)-pregnenolone,
3-(p-methoxybenzyloxy)-pregnenolone,
3-(p-bromobenzyloxy)-pregnenolone,
3-(p-methylcarboxybenzyloxy)-pregnenolone,
3-(p-methylbenzyloxy)-pregnenolone,
3-(p-fluorobenzyloxy)-pregnenolone and
3-(p-cyanobenzyloxy)-pregnenolone.
9. A pharmaceutical composition comprising a compound according to
claim 1 or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
10. A process for the manufacture of the compound of Formula I
according to claim 1, which comprises reacting a compound of
Formula III: ##STR00035## wherein R2 is as defined above, with a
compound of Formula IV: ##STR00036## wherein R1 is as defined
above, in the presence of methyl triflate and of a heterogeneous
acid scavenger or with a compound of Formula V ##STR00037## wherein
R1 is as defined above, in the presence a heterogeneous acid
scavenger.
11. The compound according to claim 1 or a pharmaceutically
acceptable salt thereof for use in a method for treatment of the
human or animal body.
12. The compound according to claim 1 or a pharmaceutically
acceptable salt thereof for use in a method for treatment of a
pathology selected from the group consisting of psychiatric and
neurological disorders; neurodegenerative disorders; metabolic
disorders; addiction, dependence, abuse relapse and related
disorders; bladder and gastrointestinal disorders; hepatic diseases
such as steatosis; non-alcoholic steatohepatitis (NASH), liver
cirrhosis; alcoholic steatosis; inflammatory diseases;
cardiovascular diseases; nephropathies; glaucoma; spasticity;
cancer; osteoporosis; obesity; autoimmune hepatitis and
encephalitis; pain or reproductive disorders and skin inflammatory
and fibrotic diseases.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to synthetic neuroactive
steroids and more particularly to synthetic Pregnenolone
derivatives and their use in a method for treatment of the human or
animal body.
BACKGROUND OF THE INVENTION
[0002] Various steroids synthesized in the adrenal glands and
gonads are capable of modulating neuron excitability in the CNS.
For these compounds the term "neuroactive steroids" has been coined
(Majewska et al., 1986), or "neurosteroids" for those that the
brain can synthesize de novo (Baulieu, 1991).
[0003] Steroid hormones have long been recognized to have sedative,
anesthetic and anti-seizure properties in animals and humans (Aird,
1944; Aird and Gordan, 1951; Gyermek et al., 1967; Green et al.,
1978). Studies during the past two decades have uncovered that
progesterone and deoxycorticosterone serve as precursors for the
endogenous neurosteroids allopregnanolone
(5.alpha.-pregnane-3.alpha.-ol-20-one) and THDOC
(5.alpha.-pregnane-3.alpha.,21-diol-20-one), respectively (Reddy,
2003; 2009a). Testosterone-derived androgens such as androstanediol
(5.alpha.-androstane-3.alpha.,17.beta.-diol) and estradiol can be
considered as neurosteroids (Reddy, 2008). Generally, the acute
effects of neurosteroids are not related to interactions with
classical steroid hormone receptors that regulate gene
transcription. Moreover, neurosteroids are not themselves active at
intracellular steroid receptors. They modulate brain excitability
primarily by interaction with neuronal membrane receptors and ion
channels, principally GABA-A receptors (Lambert et al., 2003;
Reddy, 2003; Akk et al., 2009).
[0004] In addition to endogenous steroids such as pregnenolone
sulfate. DHEA-S, estradiol, or progesterone for which neuroactive
properties have been described (Paul and Purdy, 1992; Rupprecht,
1997), synthetic steroids have been developed recently that share
their endogenous counterparts' characteristic of modulating a
variety of G-protein-coupled receptors and ligand-gated ion
channels (Gasior et al., 1999).
[0005] Some synthetic neurosteroids that show better
pharmacokinetics and efficacy are evaluated for sedative and
anxiolytic (minaxolone), anesthetic (alphaxolone) and antiepileptic
(ganaxolone) effects.
[0006] However, the diverse in vivo actions of neuroactive steroids
depend on the lack of specificity of natural and synthetic steroids
that do not bind uniquely to one neurotransmitter receptor but on
several of them. The metabolism of neuroactive steroids with
metabolites that exhibit different pharmacological profiles
compared to their precursors is also responsible for the variety of
effects of a single steroid. As yet, no derivatives of naturally
occurring or synthetic steroids have been developed that show
exclusive receptor specificity or avoid side effects due to it
metabolisation.
SUMMARY OF THE INVENTION
[0007] Among the naturally occurring steroid, studies that
demonstrate an in vivo effect by pregnenolone are very few but they
suggest a beneficial role for this steroid. It was shown that
pregnenolone administration decreased the formation of gliotic
tissue following a penetrating lesion in rat cerebral cortex and
hippocampus (Garcia-Estrada et al., 1999). Pregnenolone was showed
to protect against toxicity induced by glutamate and the protein
beta amyloid in hippocampal cells line (HT-22) cultures (Gursoy et
al., 2001). Furthermore, pregnenolone has also been suggested to
enhance memory performance (Mathis et al., 1994). However, these
effects of pregnenolone have been classically attributed to the
downstream metabolites of pregnenolone, that in itself is
considered the inactive precursor of downstream active steroids.
Thus, pregnenolone has not effects on the principal targets of
neuroactive steroids that are the GABA and Excitatory aminoacid
receptors.
[0008] Recently, the inventors have shown that pregnenolone acts as
an inhibitor of the human CB1 receptor with a pharmacological
profile different from orthosteric antagonist and from other
neuroactive steroids, which indicates that pregnenolone has less
unspecific and undesiderable effects than orthosteric antagonists
of the CB1 and other neuroactive steroids (patent application
PCT/EP2012/059310 published under WO2012/160006; Vallee et al.,
2013).
[0009] Given that pregnenolone is the first step of steroid
synthesis in the brain and other organ, pregnenolone is not
considered as a good target to derive synthetic neuroactive
steroids from.
[0010] Indeed, such pregnenolone derivatives present high risk to
be metabolised. The generated metabolites could exhibit different
pharmacological profiles compared to their precursors and exert
side effects.
[0011] The inventors have found that molecules derived from
pregnenolone that contain a 3-benzyloxy function (substituted or
not) cannot be converted into metabolites endowed with
progestative, androgenic, estrogenic, and glucocorticoid activity.
Therefore, using these pregnenolone derivatives that are not or not
substantially converted into pregnenolone metabolites avoids side
effects.
[0012] Thus, the present invention relates to a compound of Formula
I or a pharmaceutically acceptable salt thereof,
##STR00002##
[0013] wherein: [0014] R1 is:
[0015] C1-8 alkyl,
[0016] C1-8 alkoxy,
[0017] CN,
[0018] NO.sub.2,
[0019] amino,
[0020] COOH,
[0021] COOCH.sub.3
[0022] OH,
[0023] N.sub.3,
[0024] or
[0025] halogen
[0026] and [0027] R2 is:
[0028] H,
[0029] OH,
[0030] C1-8 alkyl,
[0031] C1-8 alkoxy,
[0032] C2-C6 alkenyl,
[0033] halogen,
[0034] Bn-O--
[0035] Bn- optionally substituted with C1-8 alkyl, C1-8 alkoxy, CN,
NO.sub.2, amino, COOH or halogen or
[0036] Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, CN,
NO.sub.2, amino, COOH or halogen.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0037] The term "Agonist" refers to a compound that enhances the
activity of another compound or receptor site.
[0038] The terms "Antagonist" and "Inhibitor" refer to a compound
that diminishes or prevents the activity of another compound at a
receptor site and more generally refer to a compound that
diminishes or prevents the activation and/or the activity of a
receptor.
[0039] The terms "Treatment or treating" refer to both therapeutic
treatment and prophylactic or preventive measures, wherein the
object is to prevent or slow down the targeted pathologic condition
or disorder. Those in need of treatment include those already with
the disorder as well as those prone to have the disorder or those
in whom the disorder is to be prevented. Hence, the subject to be
treated herein may have been diagnosed as having the disorder or
may be predisposed or susceptible to the disorder.
[0040] As used herein, the term "subject" denotes a mammal, such as
a rodent, a feline, a canine, and a primate. Preferably, a subject
according to the invention is a human.
[0041] A "therapeutically effective amount" is intended for a
minimal amount of active agent which is necessary to impart
therapeutic or a preventive benefit to a subject. For example, a
"therapeutically effective amount" to a mammal is such an amount
which induces, ameliorates or otherwise causes an improvement in
the pathological-symptoms, disease progression or physiological
conditions associated with or resistance to succumbing to a
disorder.
[0042] "Alkyl" means monovalent linear or branched saturated
hydrocarbon moiety, consisting solely of carbon and hydrogen atoms.
C1-8 alkyl means a linear or branched alkyl having from one to
eight carbon atoms.
[0043] "Alkoxy" means a moiety of the formula --OR, wherein R is an
alkyl moiety as defined herein.
[0044] The term "alkenyl" used herein describes an unsaturated,
linear or branched aliphatic hydrocarbon having at least one
carbon-carbon double bond. "C2-6 alkenyl" denotes a straight- or
branched-chain of 2 to 6 carbon atoms with at least one double
bond.
[0045] The term "halogen", alone or in combination with other
groups, denotes chloro (Cl), iodo (I), fluoro (F) and bromo
(Br).
[0046] The term "cyano", alone or in combination with other groups,
denotes the group --CN.
[0047] The term "hydroxyl", alone or in combination with other
groups, denotes the group --OH.
[0048] The term "nitro", alone or in combination with other groups,
denotes the group --NO.sub.2.
[0049] The term "carboxyl", alone or in combination with other
groups, denotes the group --COOH.
[0050] "Amino" means a moiety of the formula --NRR' wherein R and
R' each independently is hydrogen, or alkyl as defined herein.
[0051] The abbreviation Bn refers to a benzyl group.
[0052] The abbreviation Ph refers to a phenyl group.
[0053] The term "pharmaceutically acceptable salts" refers to salts
that are suitable for use in contact with the tissues of humans and
animals without undue toxicity, irritation, allergic response, and
the like. Examples of suitable salts include salts of alkali metals
such as potassium, sodium, lithium, salts of alkaline earth metals
such as calcium, magnesium and acid addition salts with inorganic
and organic acids are, but are not limited to, hydrochloric acid,
nitric acid, sulphuric acid, phosphoric acid, sulphuric acid,
citric acid, formic acid, fumaric acid, maleic acid, lactic acid,
malic acid, acetic acid, succinic acid, hemisuccinic acid, tartaric
acid, methane-sulfonic acid, p-toluenesulphonic acid, trifluoro
acetic acid and the like.
[0054] Substituents above the plane of the molecule are shown as a
solid line () and are described as .beta.; those below the plane
are shown by a broken line () and are described as .alpha..
[0055] Compounds of the Invention
[0056] General Formula:
[0057] The invention relates to compounds of Formula I or
pharmaceutically acceptable salts thereof:
##STR00003##
[0058] wherein: [0059] R1 is:
[0060] C1-8 alkyl,
[0061] C1-8 alkoxy,
[0062] CN,
[0063] NO.sub.2,
[0064] amino,
[0065] COOH,
[0066] COOCH.sub.3
[0067] OH,
[0068] N.sub.3,
[0069] or
[0070] halogen
[0071] and [0072] R2 is:
[0073] H,
[0074] OH,
[0075] C1-8 alkyl,
[0076] C1-8 alkoxy,
[0077] C2-C6 alkenyl,
[0078] halogen,
[0079] Bn-O--
[0080] Bn- optionally substituted with C1-8 alkyl, C1-8 alkoxy, CN,
NO.sub.2, amino, COOH or halogen
[0081] or
[0082] Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, CN,
NO.sub.2, amino, COOH or halogen.
[0083] In one preferred embodiment, R2 is in a position.
[0084] In this embodiment, the compounds of the invention have the
Formula II:
##STR00004##
[0085] wherein: [0086] R1 is:
[0087] C1-8 alkyl,
[0088] C1-8 alkoxy,
[0089] CN,
[0090] NO.sub.2,
[0091] amino,
[0092] COOH,
[0093] COOCH.sub.3,
[0094] OH,
[0095] N.sub.3,
[0096] or
[0097] halogen
[0098] and [0099] R2 is:
[0100] H,
[0101] OH,
[0102] C1-8 alkyl,
[0103] C1-8 alkoxy,
[0104] C2-C6 alkenyl,
[0105] halogen,
[0106] Bn-O--
[0107] Bn- optionally substituted with C1-8 alkyl, C1-8 alkoxy, CN,
NO.sub.2, amino, COOH or halogen
[0108] or
[0109] Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, CN,
NO), amino, COOH or halogen.
In a preferred embodiment, R1 is OH, C1-8 alkyl, C1-8 alkoxy or
halogen, more preferably R1 is OH, methyl, ethyl, methoxy, ethoxy,
methylcarboxy, Cl, Br, F or cyano. In a preferred embodiment, R2 is
H, OH, C1-8 alkyl, C1-8 alkoxy, C1-8 alkenyl or Bn, more preferably
R2 is H, OH, methyl, ethyl, methoxy, ethoxy, allyl or Bn. More
preferably, the compound of the invention is: [0110]
3-(p-hydroxybenzyloxy)-pregnenolone, [0111]
3-(p-methylbenzyloxy)-pregnenolone, [0112]
3-(p-ethylbenzyloxy)-pregnenolone, [0113]
3-(p-methoxybenzyloxy)-pregnenolone, [0114]
3-(p-ethoxybenzyloxy)-pregnenolone, [0115]
3-(p-methylcarboxybenzyloxy)-pregnenolone, [0116]
3-(p-fluorobenzyloxy)-pregnenolone, [0117]
3-(p-chlorobenzyloxy)-pregnenolone, [0118]
3-(p-bromobenzyloxy)-pregnenolone, [0119]
3-(p-cyanobenzyloxy)-pregnenolone, [0120]
17-hydroxy-3-(p-hydroxybenzyloxy)-pregnenolone, [0121]
17-hydroxy-3-(p-methylbenzyloxy)-pregnenolone, [0122]
3-(p-ethylbenzyloxy)-17-hydroxy-pregnenolone, [0123]
17-hydroxy-3-(p-methoxybenzyloxy)-pregnenolone, [0124]
3-(p-ethoxybenzyloxy)-17-hydroxy-pregnenolone, [0125]
17-hydroxy-3-(p-methylcarboxybenzyloxy)-pregnenolone, [0126]
3-(p-fluorobenzyloxy)-17-hydroxy-pregnenolone, [0127]
3-(p-chlorobenzyloxy)-17-hydroxy-pregnenolone, [0128]
3-(p-bromobenzyloxy)-17-hydroxy-pregnenolone. [0129]
3-(p-cyanobenzyloxy)-17-hydroxy-pregnenolone, [0130]
3-(p-hydroxybenzyloxy)-17-methyl-pregnenolone, [0131]
17-methyl-3-(p-methylbenzyloxy)-pregnenolone, [0132]
3-(p-ethylbenzyloxy)-17-methyl-pregnenolone, [0133]
3-(p-methoxybenzyloxy)-17-methyl-pregnenolone, [0134]
3-(p-ethoxybenzyloxy)-17-methyl-pregnenolone, [0135]
17-methyl-3-(p-methylcarboxybenzyloxy)-pregnenolone, [0136]
3-(p-fluorobenzyloxy)-17-methyl-pregnenolone, [0137]
3-(p-chlorobenzyloxy)-17-methyl-pregnenolone, [0138]
3-(p-bromobenzyloxy)-17-methyl-pregnenolone, [0139]
3-(p-cyanobenzyloxy)-17-methyl-pregnenolone, [0140]
17-ethyl-3-(p-hydroxybenzyloxy)-pregnenolone, [0141]
17-ethyl-3-(p-methylbenzyloxy)-pregnenolone, [0142]
17-ethyl-3-(p-ethylbenzyloxy)-pregnenolone, [0143]
17-ethyl-3-(p-methoxybenzyloxy)-pregnenolone, [0144]
3-(p-ethoxybenzyloxy)-17-ethyl-pregnenolone, [0145]
17-ethyl-3-(p-methylcarboxybenzyloxy)-pregnenolone, [0146]
17-ethyl-3-(p-fluorobenzyloxy)-pregnenolone, [0147]
3-(p-chlorobenzyloxy)-17-ethyl-pregnenolone, [0148]
3-(p-bromobenzyloxy)-17-ethyl-pregnenolone, [0149]
3-(p-cyanobenzyloxy)-17-ethyl-pregnenolone, [0150]
3-(p-hydroxybenzyloxy)-17-methoxy-pregnenolone, [0151]
17-methoxy-3-(p-methylbenzyloxy)-pregnenolone, [0152]
3-(p-ethylbenzyloxy)-17-methoxy-pregnenolone, [0153]
17-methoxy-3-(p-methoxybenzyloxy)-pregnenolone, [0154]
3-(p-ethoxybenzyloxy)-17-methoxy-pregnenolone, [0155]
17-methoxy-3-(p-methylcarboxybenzyloxy)-pregnenolone, [0156]
3-(p-fluorobenzyloxy)-17-methoxy-pregnenolone, [0157]
3-(p-chlorobenzyloxy)-17-methoxy-pregnenolone, [0158]
3-(p-bromobenzyloxy)-17-methoxy-pregnenolone, [0159]
3-(p-cyanobenzyloxy)-17-methoxy-pregnenolone, [0160]
17-ethoxy-3-(p-hydroxybenzyloxy)-pregnenolone, [0161]
17-ethoxy-3-(p-methylbenzyloxy)-pregnenolone, [0162]
17-ethoxy-3-(p-ethylbenzyloxy)-pregnenolone, [0163]
17-ethoxy-3-(p-methoxybenzyloxy)-pregnenolone, [0164]
17-ethoxy-3-(p-ethoxybenzyloxy)-pregnenolone, [0165]
17-ethoxy-3-(p-methylcarboxybenzyloxy)-pregnenolone, [0166]
17-ethoxy-3-(p-fluorobenzyloxy)-pregnenolone, [0167]
3-(p-chlorobenzyloxy)-17-ethoxy-pregnenolone, [0168]
3-(p-bromobenzyloxy)-17-ethoxy-pregnenolone, [0169]
3-(p-cyanobenzyloxy)-17-ethoxy-pregnenolone, [0170]
17-allyl-3-(p-hydroxybenzyloxy)-pregnenolone, [0171]
17-allyl-3-(p-methylbenzyloxy)-pregnenolone, [0172]
17-allyl-3-(p-ethylbenzyloxy)-pregnenolone, [0173]
17-allyl-3-(p-methoxybenzyloxy)-pregnenolone, [0174]
17-allyl-3-(p-ethoxybenzyloxy)-pregnenolone, [0175]
17-allyl-3-(p-methylcarboxybenzyloxy)-pregnenolone, [0176]
17-allyl-3-(p-fluorobenzyloxy)-pregnenolone, [0177]
17-allyl-3-(p-chlorobenzyloxy)-pregnenolone, [0178]
17-allyl-3-(p-bromobenzyloxy)-pregnenolone, [0179]
17-allyl-3-(p-cyanobenzyloxy)-pregnenolone, [0180]
17-benzyl-3-(p-hydroxybenzyloxy)-pregnenolone, [0181]
17-benzyl-3-(p-methylbenzyloxy)-pregnenolone, [0182]
17-benzyl-3-(p-ethylbenzyloxy)-pregnenolone, [0183]
17-benzyl-3-(p-methoxybenzyloxy)-pregnenolone, [0184]
17-benzyl-3-(p-ethoxybenzyloxy)-pregnenolone, [0185]
17-benzyl-3-(p-methylcarboxybenzyloxy)-pregnenolone, [0186]
17-benzyl-3-(p-fluorobenzyloxy)-pregnenolone [0187]
17-benzyl-3-(p-chlorobenzyloxy)-pregnenolone [0188]
17-benzyl-3-(p-bromobenzyloxy)-pregnenolone or [0189]
17-benzyl-3-(p-cyanobenzyloxy)-pregnenolone. The preferred
compounds of the invention is selected from the group consisting of
3.beta.-(p-Methoxybenzyloxy)-17.alpha.-methyl-pregnenolone,
17-benzyl-3-(p-methoxybenzyloxy)-pregnenolone,
3-(p-methoxybenzyloxy)-pregnenolone,
3-(p-bromobenzyloxy)-pregnenolone,
3-(p-methylcarboxybenzyloxy)-pregnenolone,
3-(p-methylbenzyloxy)-pregnenolone,
3-(p-fluorobenzyloxy)-pregnenolone and
3-(p-cyanobenzyloxy)-pregnenolone. The preferred compound of the
invention is
3.beta.-(p-Methoxybenzyloxy)-17.alpha.-methyl-pregnenolone. The
invention also relates to a pharmaceutical composition comprising a
compound of the invention or a pharmaceutically salt thereof and a
pharmaceutically acceptable carrier.
[0190] Process for the Manufacture
[0191] The present invention also relates to a process for the
manufacture of the compounds of the invention, which comprises
reacting a compound of Formula III:
##STR00005##
[0192] wherein R2 is as defined above,
[0193] with a compound of Formula IV:
##STR00006##
[0194] wherein R1 is as defined above,
[0195] in the presence of a heterogeneous acid scavenger and of
methyl triflate
[0196] or
[0197] with a compound of Formula V
##STR00007##
[0198] wherein R1 is as defined above
[0199] in the presence of a heterogeneous acid scavenger.
[0200] In case of a compound of formula V, there is no need for the
presence of methyl triflate due to the OTf group.
In one embodiment, the process for the manufacture of the compounds
of the invention, comprises reacting a compound of Formula III:
##STR00008##
[0201] wherein R2 is as defined above,
[0202] with a compound of Formula IV:
##STR00009##
[0203] wherein R1 is as defined above,
[0204] in the presence of a heterogeneous acid scavenger and of
methyl triflate.
In another embodiment, the process for the manufacture of the
compounds of the invention, comprises reacting a compound of
Formula III:
##STR00010##
[0205] wherein R2 is as defined above,
[0206] with a compound of Formula V
##STR00011##
[0207] wherein R1 is as defined above
[0208] in the presence of a heterogeneous acid scavenger.
[0209] Preferably, the solvent for this reaction is an aromatic
solvent such as trifluorotoluene or toluene.
[0210] Preferably, the heterogeneous acid scavenger is potassium
carbonate or magnesium oxide.
[0211] Method for synthesis of compounds of formula III are well
described in the prior art (Glazier E. R., 1962, Marshall et al.,
1948, Jones et al., 1965).
[0212] For example, synthesis of a compound of formula III wherein
R2 is an alkyl, -allyl, -benzyl or -aryl may be done by reacting
pregnenolone with Ac.sub.2O to form a enol acetate. Then, the enol
acetate is reacted with a Grignard reagent to generate an enolate
which is subsequently trapped with a halogeno-R2.
[0213] Further, for example, synthesis of a compound of formula III
wherein R2 is an alkoxy, benzyloxy or aryloxy may be is done by
reacting pregnenolone with the corresponding alcohol in the
presence of Cu.sup.2+.
[0214] Method of Treatment
[0215] The present invention also relates to a compound of the
invention as defined above or a pharmaceutically acceptable salt
thereof for use in a method for treatment of the human or animal
body.
[0216] The present invention also relates to a method for the
treatment of a pathologic condition or disorder in a subject in
need thereof comprising administering to said subject an effective
amount of a compound of the invention as defined above or a
pharmaceutically acceptable salt thereof.
[0217] The pathologies that may be treated with the compounds of
the invention are those which may be treated by Pregnenolone, for
example the pathologies that may be treated by Pregnenolone because
of it action as an inhibitor of the CB1 receptor.
[0218] Examples of such pathologies are psychiatric and
neurological disorders; neurodegenerative disorders; metabolic
disorders; addiction, dependence, abuse relapse and related
disorders; bladder and gastrointestinal disorders; hepatic diseases
such as steatosis; non-alcoholic steatohepatitis (NASH), liver
cirrhosis; alcoholic steatosis; inflammatory diseases;
cardiovascular diseases; nephropathies; glaucoma; spasticity;
cancer; osteoporosis; obesity; autoimmune hepatitis and
encephalitis; pain or reproductive disorders and skin inflammatory
and fibrotic diseases.
[0219] The present invention also relates to the use of compounds
of the invention or a pharmaceutically acceptable salt thereof for
the preparation of a medicament for treating one of the above
mentioned pathologies.
[0220] The invention will be further illustrated by the following
figures and examples. However, these examples and figures should
not be interpreted in any way as limiting the scope of the present
invention.
EXAMPLES
[0221] A. Examples of Synthesis of Pregnenolone Derivatives:
[0222] Pregnenolone is a well-known and commercially available
steroid (CAS number 145-13-1).
[0223] As shown below, Pregnenolone can be used as precursor for
the synthesis of its derivatives.
[0224] 1. Synthesis of Pregnenolone Derivatives Substituted in
C17
[0225] First, Pregnenolone is substituted in C17.
[0226] Example of Synthesis of a Pregnenolone Derivative Having C17
Substituted with R:
[0227] As shown below, to synthesize a Pregnenolone substituted
with an alkyl, an allyl or an aryl at C17 position, in a first
step, the corresponding enol acetate is formed by reacting
Pregnenolone with Ac.sub.2O. Then, the enol acetate is reacted with
a Grignard reagent such as MeMgBr in THF to generate an enolate
which is subsequently trapped with an electrophile. The
electrophile would be preferentially an R-iodo- or R-bromo wherein
R is an alkyl, -allyl, -benzyl or -aryl.
##STR00012##
[0228] Example of Synthesis of the Enol Acetate Intermediate
[0229] As shown below, p-toluenesulfonic acid monohydrate (1.12 g;
5.9 mmol; 0.93 eq.) was added to a solution of Pregnenolone (2 g;
6.3 mmol; 1 eq.) in acetic anhydride (230 ml). The reaction medium
was stirred for 5 h at reflux and acetic anhydride was slowly
distilled. After allowed to cool to 20.degree. C., the reaction
medium was poured into crushed ice then the mixture is extracted
with diethyl ether. The organic layer was washed with saturated
aqueous Na.sub.2CO.sub.3, dried over Na.sub.2SO.sub.4 then
evaporated under reduced pressure. The residue was purified by
chromatography on silica gel (eluent: cyclohexane/AcOEt from 100/0
to 90/10) to give the Pregnenolone enol acetate (2.2 g; 85%) as a
white solid.
##STR00013##
[0230] Example of Synthesis of the
17.alpha.-Methyl-Pregnenolone
[0231] As shown below, MeMgBr.sub.2 (3M in Et.sub.2O; 25 ml; 75
mmol; 10 eq.) was added to a solution of pregnenolone enol acetate
(3 g; 7.5 mmol; 1 eq.) in anhydrous THF (65 ml). The reaction
medium was stirred for 1 h at reflux, then allowed to cool to
20.degree. C. CH.sub.3I (4.6 ml; 75 mmol; 10 eq.) was added and
reaction medium was stirred at reflux. Adding CH.sub.3I was
repeated every 45 minutes until 40 equivalents. After cooling to
20.degree. C., an aqueous solution of NH.sub.4Cl is added then the
mixture is extracted with ethyl acetate. The organic layer was
washed with brine, dried over Na.sub.2SO.sub.4 then evaporated
under reduced pressure. The residue was purified by chromatography
on silica gel (eluent: cyclohexane/AcOEt 75/25) to give the
17.alpha.-methyl-pregnenolone (600 mg; 25%) as a white solid.
##STR00014##
[0232] Example of Synthesis of a Pregnenolone Derivative Having C17
Substituted with --OR
[0233] To synthesize a Pregnenolone substituted with an alkoxy-,
benzyloxy- or aryloxy- at C17 position, Pregnenolone is reacted
with the corresponding alcohol, R--OH, in the presence of
Cu.sup.2+.
##STR00015##
[0234] Example of Synthesis of 17-Methoxy-Pregnenolone:
[0235] As shown below, CuBr.sub.2 (4.05 g; 18.13 mmol; 1.9 eq.) was
added to a suspension of pregnenolone (3 g; 9.48 mmol; 1 eq.) in
methanol (360 ml). The reaction medium was stirred for 24 h at
reflux, then evaporated under reduced pressure. The residue was
dissolved in dichloromethane and water. The organic layer was
washed with brine, dried over Na.sub.2SO.sub.4 then concentrated
under reduced pressure. The residue was purified by chromatography
on silica gel (eluent: cyclohexane/AcOEt 80/20) then by
recrystallisation (acetone) to give the 17-methoxy-pregnenolone
(510 mg; 15%) as a white solid.
##STR00016##
[0236] 2. Synthesis of Compound of Formula IV
[0237] Some compounds of formula IV may be commercially available
for example 2-(4-methoxybenzyloxy)-4-methylquinoleine.
Compounds of formula IV may also be synthesized by reacting
2-chloro-4-methylquinoleine and para-substituted benzyl alcohol in
the presence of 18-crown-6 and KOH according the schema below.
##STR00017##
Example of Synthesis of 2-(p-Methylbenzyloxy)-4-Methylquinoline As
shown below, to a solution of 2-chloro-4-methylquinoleine- (500 mg;
2.8 mmol; 1 eq.) in anhydrous toluene (10 mL) was added
successively 4-methylbenzyl alcohol (409 mg, 3.35 mmol; 1.25 eq),
KOH (630 mg; 11.2 mmol; 4.0 eq.), then 18-crown-6 (45 mg, 0.16
mmol, 0.06 eq). The reaction medium was heated at reflux for 1.5 h
using a Dean-Stark trap. The reaction medium was then cooled to
room temperature then water was added and product is extracted with
AcOEt. The organic phase is dried (Na.sub.2SO.sub.4) then
evaporated under vacuum. The residue was purified by chromatography
on silica gel (eluent: cyclohexane/AcOEt 95/5) to give
2-(p-methylbenzyloxy)-4-methylquinoline (660 mg; 89%) as a
colorless oil.
##STR00018##
[0238] 3. Synthesis of Compounds of Formula V
Compounds of formula V may be synthesized in two steps: First by
reacting 2-chloropyridine and para-substituted benzyl alcohol in
the presence of 18-crown-6 and KOH or t-BuOK; Second by reacting
the resulting product with methyl triflate to allow the salt
formation according to the schema below.
##STR00019##
[0239] Example of Synthesis of
2-(p-Bromobenzyloxy)-1-Methylpyridinium Triflate:
[0240] As shown below, to a solution of 2-chloropyridine (0.9 mL;
9.6 mmol; 1.2 eq.) in anhydrous toluene (16 mL) was added
successively 4-Bromobenzyl alcohol (1.5 g, 8.0 mmol; 1 eq), KOH
(1.35 g; 24 mmol; 3.0 eq.), then 18-crown-6 (105 mg, 0.4 mmol, 0.05
eq). The reaction medium was stirred at reflux for 1 h using a
Dean-Stark trap. The reaction medium was cooled to room temperature
then water was added and product was extracted with AcOEt. The
organic phase is dried (Na.sub.2SO.sub.4) then evaporated under
vacuum. The residue was purified by chromatography on silica gel
(eluent: cyclohexane/AcOEt 9/1) to give
2-(p-Bromobenzyloxy)-pyridine (2 g; 78%) as a colorless oil.
For the second step, methyl triflate, MeOTf, (450 .mu.L; 3.97 mmol;
1.05 eq) was added to a cold solution of
2-(p-bromobenzyloxy)-pyridine (1 g; 0.3.7 mmol; 1 eq). The reaction
medium was stirred for 2 hours at room temperature then evaporated
under vacuum to give quantitatively
2-(p-Bromobenzyloxy)-1-methylpyridinium Triflate (1.6 g) as a white
solid.
##STR00020##
[0241] Example of Synthesis of
2-(p-Methylcarboxybenzyloxy)-1-Methylpyridinium Triflate:
As shown below, to a solution of 2-chloropyridine (1.13 mL; 12.0
mmol; 1.0 eq.) in anhydrous dioxane (48 mL) was added successively
4-Methylcarboxy-benzyl alcohol (1.5 g. 8.0 mmol; 1 eq) and t-BuOK
(2 g; 18 mmol; 1.5 eq.). The reaction medium was heated at reflux
for 16 h. The reaction medium was cooled to room temperature then
water was added and product is extracted with AcOEt. The organic
phase is dried (Na.sub.2SO.sub.4) then evaporated under vacuum. The
residue was purified by chromatography on silica gel (eluent:
cyclohexane/AcOEt 96/4) to give
2-(p-Methylcarboxybenzyloxy)-pyridine (1.13 g; 39%) as a colorless
oil. For the second step, MeOTf, (293 .mu.L; 2.59 mmol; 1.05 eq)
was added to a cold solution of
2-(p-Methylcarboxybenzyloxy)-pyridine (600 mg; 2.46 mmol; 1 eq).
The reaction medium was stirred for 2 hours at room temperature
then evaporated under vacuum to give quantitatively
2-(p-Methylcarboxybenzyloxy)-1-methylpyridinium Triflate (0.9 g) as
a white solid.
##STR00021##
[0242] 4. Synthesis of Pregnenolone Derivatives Having C3
Substituted with Para-Substituted Benzyloxy
[0243] Starting from Pregnenolone or Pregnenolone derivative having
the suitable group in C17, the pregnenolone or pregnenolone
derivative is substituted in C3 with a group OBn-R1 according to
known methods of benzylation of alcohol (Poon K W C. et al. 2006,
Giannis et al., 2009, Nwoye, E. O et al., 2007) and as shown
below.
##STR00022##
##STR00023##
[0244] Example of Benzylation of Pregnenolone
[0245] As shown below, MgO (46 mg; 1.14 mmol; 2 eq.) and
2-benzyloxy-1-methylpyridinium triflate (400 mg; 1.14 mmol; 2.0
eq.) were added to a solution of pregnenolone (181 mg; 0.57 mmol; 1
eq.) in trifluorotoluene (4 ml). The reaction medium was stirred
for one night at 85.degree. C., then filtered on celite and
evaporated under reduced pressure. The residue was purified by
chromatography on silica gel (eluent: cyclohexane/AcOEt 95/5) to
give the 3.beta.-benzyloxy-pregnenolone (0.16 g; 70%) as a white
solid.
##STR00024##
[0246] Example of Benzylation of 17.alpha.-Benzylpregnenolone
[0247] As shown below, MgO (16 mg; 2.42 mmol; 2.0 eq.) and
2-benzyloxymethylpyridinium triflate (1 g; 2.86 mmol; 2.0 eq.) were
added to a solution of 17.alpha.-benzylpregnenolone (580 mg; 1.43
mmol; 1 eq.) in trifluorotoluene (15 ml). The reaction medium was
stirred for one night at 85.degree. C., then filtered on celite and
evaporated under reduced pressure. The residue was purified by
chromatography on silica gel (eluent: cyclohexane/AcOEt 95/5) to
give the 3.beta.-benzyloxy-17.alpha.-benzyl-pregnenolone (300 mg;
42%) as a white solid.
##STR00025##
Example of Synthesis of the
3.beta.-(p-Bromobenzyloxy)-Pregnenolone
[0248] A shown below, to a solution of pregnenolone (477 mg; 1.51
mmol; 1 eq.) in anhydrous .alpha.,.alpha.,.alpha.-trifluorotoluene
(9 mL) was added MgO (121 mg; 3.02 mmol; 2.0 eq.) then
2-(p-Bromobenzyloxy)-1-methylpyridinium Triflate (1.29 g; 3.02
mmol; 2.0 eq.). The reaction medium was stirred for 20 h at
100.degree. C., and then filtered on celite. Water was added and
product is extracted with AcOEt. The organic phase is dried
(Na.sub.2SO.sub.4) then evaporated under vacuum. The residue was
purified by chromatography on silica gel (eluent: cyclohexane/AcOEt
96/4) then triturated with acetone to give the
3.beta.-(p-bromobenzyloxy)-pregnenolone (375 mg; 49%) as a white
solid.
##STR00026##
[0249] Example of Synthesis of
3.beta.-p-Methoxybenzyloxy)-Pregnenolone:
[0250] As shown below, to a solution of pregnenolone (250 mg; 0.79
mmol; 1 eq.) in anhydrous toluene was added successively MgO (63
mg; 1.58 mmol; 2.0 eq.), 2-(4-methoxybenzyloxy)-4-methylquinoleine
(441 mg; 1.58 mmol; 2.0 eq.) and methyl triflate (MeOTf) (180
.mu.l; 1.58 mmol; 2 eq). The reaction medium was stirred for 20 h
at 60.degree. C., and then filtered on celite. Water was added and
product is extracted with AcOEt. The organic phase is dried
(Na.sub.2SO.sub.4) then evaporated under vacuum. The residue was
purified by chromatography on silica gel (eluent: cyclohexane/AcOEt
9/1) to give the 3.beta.-(p-methoxybenzyloxy)-pregnenolone (160 mg;
43%) as a white solid.
##STR00027##
[0251] Example of Synthesis of
3.beta.-p-Methoxybenzyloxy)-17.alpha.-Methyl-Pregnenolone:
[0252] 17.alpha.-methyl-pregnenolone was synthesized as shown
above.
[0253] To a solution of 17.alpha.-methyl-pregnenolone (170 mg; 0.5
mmol; 1 eq.) in anhydrous toluene was added successively MgO (40
mg; 1 mmol; 2 eq.), 2-(4-methoxybenzyloxy)-4-methylquinoleine (290
mg; 1 mmol; 2 eq), and methyl triflate (MeOTf) (0.11 ml; 1 mmol; 2
eq). The reaction medium was stirred for one night at 85.degree.
C., and then filtered on celite. Water was added and product is
extracted with AcOEt. The organic phase is dried (Na.sub.2SO.sub.4)
then evaporated under vacuum. The residue was purified by
chromatography on silica gel (eluent: cyclohexane/AcOEt from 1/0 to
95/5) then triturated with acetone to give the
3.beta.-(p-Methoxybenzyloxy)-17.alpha.-methyl-pregnenolone (80 mg;
35%) as a white solid.
##STR00028##
[0254] Example of Synthesis of
3.beta.-(p-Methoxybenzyloxy)-17.alpha.-Benzyl-Pregnenolone:
[0255] 17.alpha.-benzyl-pregnenolone was synthesized as shown
above.
[0256] To a solution of 17.alpha.-benzyl-pregnenolone (1.9 g; 4.66
mmol; 1 eq.) in anhydrous toluene (45 ml) was added successively
MgO (373 mg; 9.3 mmol; 2 eq.),
2-(4-methoxybenzyloxy)-4-methylquinoleine (2.6 g; 9.33 mmol; 2 eq),
and methyl triflate (MeOTf) (1.06 ml; 9.33 mmol; 2 eq). The
reaction medium was stirred for one night at 40.degree. C., and
then filtered on celite. Water was added and product is extracted
with AcOEt. The organic phase is dried (Na.sub.2SO.sub.4) then
evaporated under vacuum. The residue was purified by chromatography
on silica gel (eluent: cyclohexane/AcOEt 9/1) then triturated with
acetone to give the
3.beta.-(p-methoxybenzyloxy)-17.alpha.-benzyl-pregnenolone (1.18 g;
49%) as a white solid.
##STR00029##
[0257] B. Capacity of Pregnenolone Derivatives not to be Converted
in Other Active Steroids Derived from Pregnenolone
[0258] Material and Methods
[0259] In Vitro Test of Metabolization
[0260] Alternatively the compound can be administered to any cell
line expressing the enzyme that metabolizes pregnenolone in
culture, measuring then the content of metabolites of pregnenolone
within the cell or on the cell culture medium by GC/MS and
comparing these concentrations to metabolites in cell cultures that
have been received only a vehicle or pregnenolone.
[0261] In this example, CHO cell line was used. These cells derived
from the ovary have all the enzymes needed to metabolize
pregnenolone in downstream steroids.
[0262] The content in CHO culture medium of allopregnanolone
(ALLO), epiallopregnanolone (EPIALLO), pregnenolone (PREG), DHEA,
and testosterone (TESTO) was measured by GC/MS.
[0263] Results:
[0264] Pregnenolone Derivatives for which the Transformation in
Downstream Active Steroids In Vitro is Limited.
[0265] The inventors have analyzed the metabolism of pregnenolone
derivatives using an in vitro test in CHO cells.
[0266] The administration of Pregnenolone (1 .mu.M) to these cells
for 48 hours produced a significant increase in Allopregnanolone
and Epiallopregnanolone in the culture medium (Table 1).
TABLE-US-00001 TABLE 1 Table 1: Pregnenolone metabolism ALLO
EPIALLO PREG DIIEA TESTO Control cell cultures Steroid 0.00 0.00
96.92 0.00 0.00 Pregnenolone (1 .mu.M) levels pg/ml 3529.99
16963.84 11440.66 0.00 0.00 treated cells
[0267] Pregnenolone derivatives having C3 substituted with
benzyloxy were tested using in vitro test in CHO cells.
[0268] Results are shown in Table 2 below. Results expressed as
percentage changes from CHO cells treated with Pregnenolone or as
pg/ml (0=concentrations below the detection limit).
TABLE-US-00002 TABLE 2 % changes from Reduced metabolim
Pregnenolone treated cells pg/ml N.sup.o Name Structure ALLO
EPIALLO PREG DHEA TESTO 42 3.beta.- Benzyloxy- 17.alpha.-methyl-
pregnenolone ##STR00030## -99.87 -99.94 -100.00 0.00 0.00 63
17.alpha.-Benzyl- 3.beta.- benzyloxy- pregnenolone ##STR00031##
-99.01 -99.84 -99.87 0.00 0.00 41 3.beta.- Benzyloxy- pregnenolone
##STR00032## -98.82 -99.88 -99.35 0.00 0.00 68 3.beta.- (p-methoxy-
benzyloxy)- 17.alpha.-methyl- pregnenolone ##STR00033## -100.00
-100.00 -100.00 0.00 0.00
[0269] As shown in table 2, the compound 68,
3.beta.-(p-Methoxybenzyloxy)-17.alpha.-methyl-pregnenolone, is not
metabolised in Pregnenolone and the compounds 63 and 41 are not
significantly metabolized in Pregnenolone (metabolization
<1%).
[0270] Pregnenolone derivatives that contain a 3-benzyloxy function
(substituted or not) show no detectable metabolization of
derivative of Pregnenolone in DHEA and Testosterone and very low
metabolization in Allopregnanolone and Epiallopregnanolone.
[0271] These results show the presence of a OBn-R group in C3 avoid
the conversion of Pregnenolone derivatives into Pregnenolone and
Pregnenolone metabolites, in particular metabolites whose
Pregnenolone is precursor and that are endowed with progestative,
androgenic, estrogenic, glucocorticoid activity, or neuromodulatory
properties.
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[0272] Throughout this application, various references describe the
state of the art to which this invention pertains. The disclosures
of these references are hereby incorporated by reference into the
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